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Zhang L, Wang X, Gao G, Bian Z, Kong L. SSE-Net: A novel network based on sequence spatial equation for Camellia sinensis lysine acetylation identification. Comput Biol Chem 2025; 117:108442. [PMID: 40174510 DOI: 10.1016/j.compbiolchem.2025.108442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/25/2025] [Accepted: 03/22/2025] [Indexed: 04/04/2025]
Abstract
Lysine acetylation (Kace) is one of the most important post-translational modifications. It is key to identify Kace sites for understanding regulation mechanisms in Camellia sinensis. In this study, we defined a mathematical formula, named sequence spatial equation (SSE), which could give each amino acid coordinate in 3-D space by rotating and translating. Based on SSE, an optional network SSE-Net was constructed for representing spatial structure information. Centrality metrics of SSE-Net were used to design structure feature vectors for reflecting the importance of sites. The optimal features were fed into classifier to construct model SSE-ET. The results showed that SSE-ET outperformed the other classifiers. Meanwhile, all MCC results were higher than 0.7 for different machine learning, which indicated that SSE-Net was effective for representing Kace sites in Camellia sinensis. Moreover, we implemented the other models on our dataset. The results of comparison showed that SSE-ET was much more powerful than the others. Specifically, the result of SN was nearly 20 % higher than the other models. These results showed that the proposed SSE was a valuable mathematics concept for reflecting 3-D space Kace site information in Camellia sinensis, and SSE-Net may be an essential complementary for biology and bioinformatics research.
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Affiliation(s)
- Lichao Zhang
- School of Mathematics and Statistics, Northeastern University at Qinhuangdao, Qinhuangdao, PR China; Hebei Innovation Center for Smart Perception and Applied Technology of Agricultural Data, Qinhuangdao, PR China.
| | - Xue Wang
- School of Mathematics and Statistics, Northeastern University at Qinhuangdao, Qinhuangdao, PR China
| | - Ge Gao
- School of Mathematics and Statistics, Northeastern University at Qinhuangdao, Qinhuangdao, PR China
| | - Zhengyan Bian
- School of Mathematics and Statistics, Northeastern University at Qinhuangdao, Qinhuangdao, PR China
| | - Liang Kong
- Hebei Innovation Center for Smart Perception and Applied Technology of Agricultural Data, Qinhuangdao, PR China; School of Mathematics and Information Science & Technology, Hebei Normal University of Science & Technology, Qinhuangdao, PR China
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2
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Geng X, Li M, Zhang L, Cai Y, Chen X, Mu X, Wang J, Liu B. P5CS deacetylation mediated by SIRT2 facilitates tumor growth by enhancing mitochondrial respiration in hepatocellular carcinoma. Oncogene 2025:10.1038/s41388-025-03456-3. [PMID: 40425834 DOI: 10.1038/s41388-025-03456-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 05/05/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025]
Abstract
Cancer cells typically exhibit enhanced mitochondrial metabolism to fulfill their energy and biosynthetic demands for growth. The mitochondrial response to fluctuations in cellular energy demand is essential for cellular adaptation and proper organ function. The mitochondrial delta-1-pyrroline-5-carboxylate synthase (P5CS) encoded by the ALDH18A1 gene, the key enzyme for proline synthesis, is frequently up-regulated during tumor development. However, the regulatory mechanisms governing P5CS activity in the occurrence and development of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we observe that P5CS is highly expressed in HCC tissues, and elevated levels of P5CS expression are associated with poor prognosis in HCC patients. Notably, the knockdown of P5CS inhibits the proliferation, migratory and invasive capabilities of HCC cells by reducing mitochondrial respiration. Furthermore, we demonstrate that SIRT2 interacts with P5CS and mediates the deacetylation of P5CS at lysines K311 and K347, thereby activating its enzymatic activity. Activated P5CS significantly enhances mitochondrial respiration, which supports the proliferation and tumorigenesis of HCC cells. In addition, SIRT2 knockdown inhibits the proliferation, migratory and invasive capabilities of HCC cells. These observations suggest that SIRT2-mediated P5CS deacetylation is a crucial signaling event through which cancer cells sustain mitochondrial respiration and promote HCC progression. This finding offers the potential for targeting SIRT2-mediated P5CS deacetylation as a therapeutic strategy for HCC.
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Affiliation(s)
- Xiaofang Geng
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
| | - Mengyao Li
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Lu Zhang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Yihan Cai
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Xin Chen
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Xiayue Mu
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China
| | - Jie Wang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
| | - Bowen Liu
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
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3
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Xie Y, Cai N, Liu X, He L, Ma Y, Yan C, Liang J, Ouyang SH, Luo A, He Y, Lu J, Ao D, Liu J, Ye Z, Liu B, He RR, Li W. SIRT5: a potential target for discovering bioactive natural products. J Nat Med 2025; 79:441-464. [PMID: 39979670 PMCID: PMC12058867 DOI: 10.1007/s11418-024-01871-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 12/17/2024] [Indexed: 02/22/2025]
Abstract
Silent information regulator 5 (SIRT5) is the fifth member of the sirtuin family, which is mainly expressed in mitochondrial matrix. SIRT5 plays a key role in metabolism and antioxidant responses, and is an important regulator for maintaining intracellular homeostasis. Given its involvement in multiple cellular processes, dysregulation of SIRT5 activity is associated with a variety of diseases. This review explores the structural characteristics of SIRT5 that influence its substrate specificity, highlights recent research advances, and summarizes its four key enzymatic activities along with their corresponding substrates in disease contexts. We also discuss the natural products that modulate SIRT5 activity and identify potential targets of SIRT5 through virtual docking, which may provide new therapeutic avenues. Although the mechanism of SIRT5 in diseases needs to be further elucidated and deglutathionylation activities are still at an early stage, targeting SIRT5 and its substrates holds significant promise for the development of novel therapeutics.
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Affiliation(s)
- Yuwei Xie
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Nali Cai
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiaohua Liu
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Liangliang He
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China
| | - Yiming Ma
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Changyu Yan
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China
| | - Juan Liang
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Shu-Hua Ouyang
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China
| | - Ao Luo
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yingzhi He
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Jun Lu
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Dang Ao
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Jia Liu
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Zhonglv Ye
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Bin Liu
- Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Rong-Rong He
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China.
| | - Wen Li
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Chang S, Yang Q, Chu W, Liu X, Li J, Liu Z, Lin J, Liu D, Zhao D, Peng X, Xin M, Yao Y, Xie X, Peng H, Ni Z, Sun Q, Hu Z. Lysine deacetylase TaSRT1 mediates wheat drought tolerance by deacetylating TaDT-A to reduce its protein stability and transcriptional activity. PLANT BIOTECHNOLOGY JOURNAL 2025; 23:1650-1667. [PMID: 39977256 PMCID: PMC12018820 DOI: 10.1111/pbi.14613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/26/2024] [Accepted: 01/22/2025] [Indexed: 02/22/2025]
Abstract
Drought is one of the major environmental stresses limiting crop growth and yield. Epigenetic regulations play crucial roles in plant adaptation to environmental changes, whereas the epigenetic mechanism of drought resistance in crops remains largely elusive. Here, we report that the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase TaSRT1 negatively regulates drought tolerance in wheat. Compared with the wild type, the tasrt1 mutant had higher relative water contents, along with a smaller stomatal aperture and improved water use efficiency under drought conditions, whereas TaSRT1 overexpression plants exhibited opposite phenotypes. TaSRT1 directly interacted with the drought-resistant pivotal factor TaDT-A to regulate its protein stability and transcriptional activity through lysine deacetylation. Furthermore, the key lysine residue of TaDT-A was identified as a deacetylation/acetylation site that plays an important role in regulating its stability. In addition, genetic analysis indicated TaDT-A functions downstream of TaSRT1 to modulate drought resistance. These findings uncover how the functional interplay between epigenetic regulator and transcription factors regulates drought resistance in plants, and illustrate a mechanism by which lysine deacetylase affects gene transcription via influencing non-histone protein acetylation and regulating their function.
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Affiliation(s)
- Shumin Chang
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Qun Yang
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Wei Chu
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Xingbei Liu
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Jinpeng Li
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Zehui Liu
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Jingchen Lin
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Debiao Liu
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Danyang Zhao
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Xiao Peng
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Mingming Xin
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Yingyin Yao
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Xiaodong Xie
- International Joint Center for the Mechanismic Dissection and Genetic Improvement of Crop Stress Tolerance, College of Agriculture & Resources and Environmental SciencesTianjin Agricultural UniversityTianjinChina
| | - Huiru Peng
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Zhongfu Ni
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Qixin Sun
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
| | - Zhaorong Hu
- Frontiers Science Center for Molecular Design Breeding/Key Laboratory of Crop Heterosis and Utilization (MOE)/College of Agronomy and BiotechnologyChina Agricultural UniversityBeijingChina
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5
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Jia Y, Ye M, Bukulmez O, Norman RJ, Liu W, Chen M. Melatonin Rescues Hyperacetylation of Liver and Impaired Enzymatic Activities of Mitochondrial in IVF Offspring. Reprod Sci 2025:10.1007/s43032-025-01846-2. [PMID: 40246783 DOI: 10.1007/s43032-025-01846-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 03/07/2025] [Indexed: 04/19/2025]
Abstract
Increased risks of obesity and abnormal glucose metabolism were observed in IVF offspring. However, the underlying molecular mechanism was still unclear. As an important post-translational modification (PTM), lysine acetylation changed with the changes in the metabolic environment and usually occurred on metabolic enzymes to regulate metabolic pathways and enzyme activities and participated in the regulation of downstream metabolites. In our previous study, we proved that supplementation of melatonin in the culture medium improved obesity and metabolic dysfunction in IVF mice. In this study, we further demonstrated that elevated levels of protein acetylation in hepatic cells might be associated with impaired glucose metabolism in IVF offspring, and melatonin could significantly reduce the acetylation level and improve the adverse phenotype of IVF mice. More importantly, we discovered that the supplementation of melatonin in the culture medium during in vitro fertilization significantly enhanced the activity of enzymes, especially citrate synthase (CS) and isocitrate dehydrogenase (IDH) which were involved in tricarboxylic acid recycling and played critical roles in glucose metabolism of liver. Thus, our findings elucidated a new perspective on the mechanisms of metabolic reprogramming of IVF mice.
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Affiliation(s)
- Yanping Jia
- Centre for Assisted Reproduction, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 Gaoke West Road, Pudong District, Shanghai, 201204, China
| | - Mingming Ye
- Centre for Assisted Reproduction, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 Gaoke West Road, Pudong District, Shanghai, 201204, China
| | - Orhan Bukulmez
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert J Norman
- Robinson Research Institute, School of Paediatrics and Reproductive Health, the University of Adelaide, Adelaide, SA, Australia
| | - Wenqiang Liu
- Centre for Assisted Reproduction, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 Gaoke West Road, Pudong District, Shanghai, 201204, China.
| | - Miaoxin Chen
- Centre for Assisted Reproduction, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 Gaoke West Road, Pudong District, Shanghai, 201204, China.
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6
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O’Keefe S, Wang Q. ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non-small cell lung cancer. J Clin Invest 2025; 135:e191094. [PMID: 40166937 PMCID: PMC11957684 DOI: 10.1172/jci191094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Non-small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.
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Affiliation(s)
- Sophie O’Keefe
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- University of Virginia Comprehensive Cancer Center, Charlottesville, Virginia, USA
| | - Qiwei Wang
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- University of Virginia Comprehensive Cancer Center, Charlottesville, Virginia, USA
- Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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7
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Strzałka P, Krawiec K, Wiśnik A, Jarych D, Czemerska M, Zawlik I, Pluta A, Wierzbowska A. The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia-A Promising Road Ahead. Cancers (Basel) 2025; 17:1009. [PMID: 40149343 PMCID: PMC11940623 DOI: 10.3390/cancers17061009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Acute myeloid leukemia (AML) corresponds to a heterogeneous group of clonal hematopoietic diseases, which are characterized by uncontrolled proliferation of malignant transformed myeloid precursors and their inability to differentiate into mature blood cells. The prognosis of AML depends on many variables, including the genetic features of the disease. Treatment outcomes, despite the introduction of new targeted therapies, are still unsatisfactory. Recently, there have been an increasing number of reports on enzymatic proteins of the sirtuin family and their potential importance in cancer in general. Sirtuins are a group of 7 (SIRT1-7) NAD+-dependent histone deacetylases with pleiotropic effects on metabolism, aging processes, and cell survival. They are not only responsible for post-translational modification of histones but also play various biochemical functions and interact with other proteins regulating cell survival, such as p53. Thus, their role in key mechanisms of tumorigenesis makes them a worthwhile topic in AML. Different sirtuins have been shown to act oppositely depending on the biological context, the mechanism of which requires further exploration. This review provides a comprehensive description of the significance and role of sirtuins in AML in light of the current state of knowledge. It focuses in particular on molecular mechanisms regulated by sirtuins and signaling pathways involved in leukemogenesis, as well as clinical aspects and potential therapeutic targets in AML.
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Affiliation(s)
- Piotr Strzałka
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
| | - Kinga Krawiec
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
| | - Aneta Wiśnik
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
| | - Dariusz Jarych
- Laboratory of Virology, Institute of Medical Biology, Polish Academy of Sciences, 93-232 Lodz, Poland;
| | - Magdalena Czemerska
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
| | - Izabela Zawlik
- Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland
| | - Agnieszka Pluta
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
| | - Agnieszka Wierzbowska
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (K.K.)
- Copernicus Memorial Multi-Specialist Oncology and Trauma Center, 93-510 Lodz, Poland
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Zhu TY, Chen SY, Zhang M, Li H, Wu T, Ajiboye E, Wang JW, Jin BK, Liu DD, Zhou X, Huang H, Wan X, Sun K, Lu P, Fu Y, Yuan Y, Song H, Sablina AA, Tong C, Zhang L, Wu M, Wu H, Yang B. Genetically encoding ε-N-methacryllysine into proteins in live cells. Nat Commun 2025; 16:2623. [PMID: 40097432 PMCID: PMC11914497 DOI: 10.1038/s41467-025-57969-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 01/30/2025] [Indexed: 03/19/2025] Open
Abstract
Lysine acylation is a ubiquitous post-translational modification (PTM) that plays pivotal roles in various cellular processes, such as transcription, metabolism, protein localization and folding. Thousands of lysine acylation sites have been identified based on advances in antibody enrichment strategies, highly sensitive analysis by mass spectrometry (MS), and bioinformatics. However, only 27 lysine methacrylation (Kmea) sites have been identified exclusively in histone proteins. It is hard to separate, purify and differentiate the Kmea modification from its structural isomer lysine crotonylation (Kcr) using general biochemical approaches. Here, we identify Kmea sites on a non-histone protein, Cyclophillin A (CypA). To investigate the functions of Kmea in CypA, we develop a general genetic code expansion approach to incorporate a non-canonical amino acid (ncAA) ε-N-Methacryllysine (MeaK) into target proteins and identify interacting proteins of methacrylated CypA using affinity-purification MS. We find that Kmea at CypA site 125 regulates cellular redox homeostasis, and HDAC1 is the regulator of Kmea on CypA. Moreover, we discover that genetically encode Kmea can be further methylated to ε-N-methyl-ε-N-methacrylation (Kmemea) in live cells.
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Affiliation(s)
- Tian-Yi Zhu
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Shi-Yi Chen
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Mengdi Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Heyu Li
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Ting Wu
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Emmanuel Ajiboye
- Department of Chemistry and Biochemistry, Wichita State University, Wichita, KS, USA
| | - Jia Wen Wang
- Department of Chemistry and Biochemistry, Wichita State University, Wichita, KS, USA
| | - Bi-Kun Jin
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Dan-Dan Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xintong Zhou
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - He Huang
- Computational Medicine Beijing Co. Ltd., Beijing, China
| | - Xiaobo Wan
- Computational Medicine Beijing Co. Ltd., Beijing, China
| | - Ke Sun
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Peilong Lu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Yaxin Fu
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Ying Yuan
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hai Song
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Anna A Sablina
- VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium
| | - Chao Tong
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Long Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
| | - Ming Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Haifan Wu
- Department of Chemistry and Biochemistry, Wichita State University, Wichita, KS, USA.
| | - Bing Yang
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
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9
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Sood V, Holewinski R, Andresson T, Larson DR, Misteli T. Identification of molecular determinants of gene-specific bursting patterns by high-throughput imaging screens. Mol Cell 2025; 85:913-928.e8. [PMID: 39978338 PMCID: PMC11890955 DOI: 10.1016/j.molcel.2025.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/06/2024] [Accepted: 01/21/2025] [Indexed: 02/22/2025]
Abstract
Stochastic transcriptional bursting is a universal property of active genes. While different genes exhibit distinct bursting patterns, the molecular mechanisms that govern gene-specific stochastic bursting are largely unknown. We have developed a high-throughput-imaging-based screening strategy to identify cellular factors that determine the bursting patterns of native genes in human cells. We identify protein acetylation as a prominent effector of burst frequency and burst size acting via decreasing off-times and gene-specific changes in the on-time. These effects are not correlated with promoter acetylation. Instead, we demonstrate acetylation of the Integrator complex as a key determinant of gene bursting that alters Integrator interactions with transcription elongation and RNA processing factors but without affecting pausing. Our results suggest a prominent role for non-histone acetylation of a transcription cofactors as a mechanism for modulation of bursting via a far-downstream checkpoint.
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Affiliation(s)
- Varun Sood
- National Cancer Institute, Bethesda, MD, USA
| | - Ronald Holewinski
- Protein Characterization Laboratory, National Cancer Institute, Frederick, MD, USA
| | - Thorkell Andresson
- Protein Characterization Laboratory, National Cancer Institute, Frederick, MD, USA
| | | | - Tom Misteli
- National Cancer Institute, Bethesda, MD, USA.
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10
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Xu J, Liang C, Yao S, Wang F. Melatonin Exerts Positive Effects on Sepsis Through Various Beneficial Mechanisms. Drug Des Devel Ther 2025; 19:1333-1345. [PMID: 40026332 PMCID: PMC11871935 DOI: 10.2147/dddt.s509735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 02/12/2025] [Indexed: 03/05/2025] Open
Abstract
In recent years, our understanding of sepsis has greatly advanced. However, due to the complex pathological and physiological mechanisms of sepsis, the mechanisms of sepsis are currently not fully elucidated, and it is difficult to translate the research results into specific sepsis treatment methods. Melatonin possesses broad anti-inflammatory, antioxidant, and immune-regulatory properties, making it a promising therapeutic agent for sepsis. In recent years, further research has deepened our understanding of the potential mechanisms and application prospects of melatonin in sepsis. The mechanisms underlying the protective effects of melatonin in sepsis are multifaceted. In this review, based on a substantial body of clinical trials and animal research findings, we first highlighted the significance of melatonin as an important biomarker for disease progression and prognosis in sepsis. We also described the extensive regulatory mechanisms of melatonin in sepsis-induced organ damage. In addition to its broad anti-inflammatory, and anti-oxidant effects, melatonin exerts positive effects by regulating metabolic disorders, hemodynamics, cell autophagy, cellular ion channels, endothelial cell permeability, ferroptosis and other complex pathological mechanisms. Furthermore, as a safe exogenous supplement with low toxicity, melatonin demonstrates positive synergistic effects with other anti-sepsis agents. In the face of the urgent medical challenge of transforming the increasing knowledge of sepsis molecular mechanisms into therapeutic interventions to improve patient prognosis, melatonin seems to be a promising option.
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Affiliation(s)
- Jing Xu
- Department of Critical Care Medicine, Capital Medical University Electric Power Teaching Hospital/State Grid Beijing Electric Power Hospital, Beijing, People’s Republic of China
| | - Cui Liang
- Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China
| | - Shanglong Yao
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Fuquan Wang
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, People’s Republic of China
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11
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Gupta S, Hui SP. Epigenetic Cross-Talk Between Sirt1 and Dnmt1 Promotes Axonal Regeneration After Spinal Cord Injury in Zebrafish. Mol Neurobiol 2025; 62:2396-2419. [PMID: 39110393 DOI: 10.1007/s12035-024-04408-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/28/2024] [Indexed: 01/28/2025]
Abstract
Though spinal cord injury (SCI) causes irreversible sensory and motor impairments in human, adult zebrafish retain the potent regenerative capacity by injury-induced proliferation of central nervous system (CNS)-resident progenitor cells to develop new functional neurons at the lesion site. The hallmark of SCI in zebrafish lies in a series of changes in the epigenetic landscape, specifically DNA methylation and histone modifications. Decoding the post-SCI epigenetic modifications is therefore critical for the development of therapeutic remedies that boost SCI recovery process. Here, we have studied on Sirtuin1 (Sirt1), a non-classical histone deacetylase that potentially plays a critical role in neural progenitor cells (NPC) proliferation and axonal regrowth following SCI in zebrafish. We investigated the role of Sirt1 in NPC proliferation and axonal regrowth in response to injury in the regenerating spinal cord and found that Sirt1 is involved in the induction of NPC proliferation along with glial bridging during spinal cord regeneration. We also demonstrate that Sirt1 plays a pivotal role in regulating the HIPPO pathway through deacetylation-mediated inactivation of Dnmt1 and subsequent hypomethylation of yap1 promoter, leading to the induction of ctgfa expression, which drives the NPC proliferation and axonal regrowth to complete the regenerative process. In conclusion, our study reveals a novel cross-talk between two important epigenetic effectors, Sirt1 and Dnmt1, in the context of spinal cord regeneration, establishing a previously undisclosed relation between Sirt1 and Yap1 which provides a deeper understanding of the underlying mechanisms governing injury-induced NPC proliferation and axonal regrowth. Therefore, we have identified Sirt1 as a novel, major epigenetic regulator of spinal cord regeneration by modulating the HIPPO pathway in zebrafish.
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Affiliation(s)
- Samudra Gupta
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India
| | - Subhra Prakash Hui
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India.
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12
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Westerveld M, Besermenji K, Aidukas D, Ostrovitsa N, Petracca R. Cracking Lysine Crotonylation (Kcr): Enlightening a Promising Post-Translational Modification. Chembiochem 2025; 26:e202400639. [PMID: 39462860 PMCID: PMC11776371 DOI: 10.1002/cbic.202400639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/28/2024] [Indexed: 10/29/2024]
Abstract
Lysine crotonylation (Kcr) is a recently discovered post-translational modification (PTM). Both histone and non-histone Kcr-proteins have been associated with numerous diseases including cancer, acute kidney injury, HIV latency, and cardiovascular disease. Histone Kcr enhances gene expression to a larger extend than the extensively studied lysine acetylation (Kac), suggesting Kcr as a novel potential therapeutic target. Although numerous scientific reports on crotonylation were published in the last years, relevant knowledge gaps concerning this PTM and its regulation still remain. To date, only few selective Kcr-interacting proteins have been identified and selective methods for the enrichment of Kcr-proteins in chemical proteomics analysis are still lacking. The development of new techniques to study this underexplored PTM could then clarify its function in health and disease and hopefully accelerate the development of new therapeutics for Kcr-related disease. Herein we briefly review what is known about the regulation mechanisms of Kcr and the current methods used to identify Kcr-proteins and their interacting partners. This report aims to highlight the significant potential of Kcr as a therapeutic target and to identify the existing scientific gaps that new research must address.
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Affiliation(s)
- Marinda Westerveld
- Department of Pharmaceutical SciencesFaculty of ScienceUtrecht UniversityDavid De Wied Building, Universiteitsweg 993584 CGUtrechtNL
| | - Kosta Besermenji
- Department of Pharmaceutical SciencesFaculty of ScienceUtrecht UniversityDavid De Wied Building, Universiteitsweg 993584 CGUtrechtNL
| | - David Aidukas
- Department of Pharmaceutical SciencesFaculty of ScienceUtrecht UniversityDavid De Wied Building, Universiteitsweg 993584 CGUtrechtNL
| | - Nikita Ostrovitsa
- Trinity Biomedical Sciences Institute (TBSI)Trinity College Dublin (TCD)152-160 Pearse St.DublinD02 R590Ireland
| | - Rita Petracca
- Department of Pharmaceutical SciencesFaculty of ScienceUtrecht UniversityDavid De Wied Building, Universiteitsweg 993584 CGUtrechtNL
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13
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Chung CR, Tang Y, Chiu YP, Li S, Hsieh WK, Yao L, Chiang YC, Pang Y, Chen GT, Chou KC, Paik YS, Tran P, Lin CP, Kao YM, Chen YJ, Chang WC, Hsu JK, Horng JT, Lee TY. dbPTM 2025 update: comprehensive integration of PTMs and proteomic data for advanced insights into cancer research. Nucleic Acids Res 2025; 53:D377-D386. [PMID: 39526378 PMCID: PMC11701562 DOI: 10.1093/nar/gkae1005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/08/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Post-translational modifications (PTMs) are essential for modulating protein function and influencing stability, activity and signaling processes. The dbPTM 2025 update significantly expands the database to include over 2.79 million PTM sites, of which 2.243 million are experimentally validated from 48 databases and over 80 000 research articles. This version integrates proteomic data from 13 cancer types, with a particular focus on phosphoproteomic data and kinase activity profiles, allowing the exploration of personalized phosphorylation patterns in tumor samples. Integrating kinase-substrate phosphorylations with E3 ligase-substrate interactions, dbPTM 2025 provides a detailed map of PTM regulatory networks, offering insights into cancer-specific post-translational regulations. This update also includes advanced search capabilities, enabling users to efficiently query PTM data across species, PTM types and modified residues. The platform's new features-interactive visualization tools and streamlined data downloads-allow researchers to access and analyze PTM data easily. dbPTM 2025 also enhances functional annotations, regulatory networks and disease associations, broadening its application for cancer research and the study of disease-associated PTMs. Through these enhancements, dbPTM 2025 is a comprehensive, user-friendly resource, facilitating the study of PTMs and their roles in cancer research. The database is now freely accessible at https://biomics.lab.nycu.edu.tw/dbPTM/.
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Affiliation(s)
- Chia-Ru Chung
- Department of Computer Science and Information Engineering, National Central University, No. 300, Zhongda Rd., Zhongli Dist., Taoyuan City 320317, Taiwan
| | - Yun Tang
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Yen-Peng Chiu
- Institute of Data Science and Engineering, College of Computer Science, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Shangfu Li
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, No. 2001, Longxiang Boulevard, Longgang Dist., Shenzhen, Guangdong 518172, China
| | - Wen-Kai Hsieh
- Department of Computer Science and Information Engineering, National Central University, No. 300, Zhongda Rd., Zhongli Dist., Taoyuan City 320317, Taiwan
| | - Lantian Yao
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, No. 2001, Longxiang Boulevard, Longgang Dist., Shenzhen, Guangdong 518172, China
| | - Ying-Chih Chiang
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, No. 2001, Longxiang Boulevard, Longgang Dist., Shenzhen, Guangdong 518172, China
| | - Yuxuan Pang
- Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Guan-Ting Chen
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Kai-Chen Chou
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - You Sheng Paik
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Phuong Lam Tran
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Cheng-Pei Lin
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Yu-Min Kao
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Yi-Jie Chen
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
| | - Wen-Chi Chang
- Institute of Tropical Plant Sciences and Microbiology, National Cheng Kung University, No.1, University Rd., Tainan City 70101, Taiwan
| | - Justin Bo-Kai Hsu
- Department of Computer Science and Engineering, Yuan Ze University, No. 135, Yuandong Rd., Zhongli Dist., Taoyuan City 320315, Taiwan
| | - Jorng-Tzong Horng
- Department of Computer Science and Information Engineering, National Central University, No. 300, Zhongda Rd., Zhongli Dist., Taoyuan City 320317, Taiwan
| | - Tzong-Yi Lee
- Institute of Bioinformatics and Systems Biology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu City 300093, Taiwan
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14
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Bao C, Ma Q, Ying X, Wang F, Hou Y, Wang D, Zhu L, Huang J, He C. Histone lactylation in macrophage biology and disease: from plasticity regulation to therapeutic implications. EBioMedicine 2025; 111:105502. [PMID: 39662177 PMCID: PMC11697715 DOI: 10.1016/j.ebiom.2024.105502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/10/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024] Open
Abstract
Epigenetic modifications have been identified as critical molecular determinants influencing macrophage plasticity and heterogeneity. Among these, histone lactylation is a recently discovered epigenetic modification. Research examining the effects of histone lactylation on macrophage activation and polarization has grown substantially in recent years. Evidence increasingly suggests that lactate-mediated changes in histone lactylation levels within macrophages can modulate gene transcription, thereby contributing to the pathogenesis of various diseases. This review provides a comprehensive analysis of the role of histone lactylation in macrophage activation, exploring its discovery, effects, and association with macrophage diversity and phenotypic variability. Moreover, it highlights the impact of alterations in macrophage histone lactylation in diverse pathological contexts, such as inflammation, tumorigenesis, neurological disorders, and other complex conditions, and demonstrates the therapeutic potential of drugs targeting these epigenetic modifications. This mechanistic understanding provides insights into the underlying disease mechanisms and opens new avenues for therapeutic intervention.
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Affiliation(s)
- Chuncha Bao
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, PR China
| | - Qing Ma
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xihong Ying
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Fengsheng Wang
- State Key Laboratory of NBC Protection for Civilian, Beijing 102205, PR China
| | - Yue Hou
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, PR China
| | - Dun Wang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, PR China
| | - Linsen Zhu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, PR China
| | - Jiapeng Huang
- Clinical Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China.
| | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, PR China.
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15
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Beloborodova NV, Fedotcheva NI. Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization. Metabolites 2024; 14:703. [PMID: 39728484 DOI: 10.3390/metabo14120703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied. METHODS In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods. RESULTS It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5-1 mM decreased the respiratory control and the swelling rate by 20-30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor. CONCLUSIONS The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions.
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Affiliation(s)
- Natalia V Beloborodova
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka St., 25-2, Moscow 107031, Russia
| | - Nadezhda I Fedotcheva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya St., 3, Pushchino 142290, Russia
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16
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Yang Y, Chen Q, Fan S, Lu Y, Huang Q, Liu X, Peng X. Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation. Redox Rep 2024; 29:2312320. [PMID: 38329114 PMCID: PMC10854458 DOI: 10.1080/13510002.2024.2312320] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024] Open
Abstract
Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.
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Affiliation(s)
- Yongjun Yang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qian Chen
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Shijun Fan
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Yongling Lu
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qianyin Huang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Xin Liu
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Xi Peng
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
- State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), ChongqingPeople’s Republic of China
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17
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Pham L, Arroum T, Wan J, Pavelich L, Bell J, Morse PT, Lee I, Grossman LI, Sanderson TH, Malek MH, Hüttemann M. Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer. Redox Biol 2024; 78:103426. [PMID: 39566165 PMCID: PMC11617887 DOI: 10.1016/j.redox.2024.103426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/04/2024] [Accepted: 11/09/2024] [Indexed: 11/22/2024] Open
Abstract
Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.
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Affiliation(s)
- Lucynda Pham
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Junmei Wan
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Lauren Pavelich
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
| | - Jamie Bell
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Division of Pediatric Critical Care, Children's Hospital of Michigan, Central Michigan University, Detroit, MI, 48201, USA.
| | - Paul T Morse
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Icksoo Lee
- College of Medicine, Dankook University, Cheonan-si, 31116, Republic of Korea.
| | - Lawrence I Grossman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Thomas H Sanderson
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
| | - Moh H Malek
- Department of Health Care Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, 48201, USA.
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
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18
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Kong X, Wang W, Chen S, Song M, Zhi Y, Cai Y, Zhang H, Shen X. Comparative study of lysine acetylation in Vesicomyidae clam Archivesica marissinica and the manila clam Ruditapes philippinarum: adaptation mechanisms in cold seep environments. BMC Genomics 2024; 25:1006. [PMID: 39465380 PMCID: PMC11514971 DOI: 10.1186/s12864-024-10916-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 10/17/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND The deep-sea cold seep zone is characterized by high pressure, low temperature, darkness, and oligotrophy. Vesicomyidae clams are the dominant species within this environment, often forming symbiotic relationships with chemosynthetic microbes. Understanding the mechanisms by which Vesicomyidae clams adapt to the cold seep environment is significant. Acetylation modification of lysine is known to play a crucial role in various metabolic processes. Consequently, investigating the role of lysine acetylation in the adaptation of Vesicomyidae clams to deep-sea environments is worthwhile. So, a comparative study of lysine acetylation in cold seep clam Archivesica marissinica and shallow water shellfish Ruditapes philippinarum was conducted. RESULTS A total of 539 acetylated proteins were identified with 1634 acetylation sites. Conservative motif enrichment analysis revealed that the motifs -KacR-, -KacT-, and -KacF- were the most conserved. Subsequent gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were conducted on significantly differentially expressed acetylated proteins. The GO enrichment analysis indicated that acetylated proteins are crucial in various biological processes, including cellular response to stimulation, and other cellular processes ( p < 0.05 and false discovery rate (FDR) < 0.25). The results of KEGG enrichment analysis indicated that acetylated proteins are involved in various cellular processes, including tight junction, motor proteins, gap junction, phagosome, cGMP-PKG signaling pathways, endocytosis, glycolysis/gluconeogenesis, among others (p < 0.05 and FDR < 0.25). Notably, a high abundance of lysine acetylation was observed in the glycolysis/glycogenesis pathways, and the acetylation of glyceraldehyde 3-phosphate dehydrogenase might facilitate ATP production. Subsequent investigation into acetylation modifications associated with deep-sea adaptation revealed the specific identification of key acetylated proteins. Among these, the adaptation of cold seep clam hemoglobin and heat shock protein to high hydrostatic pressure and low temperature might involve an increase in acetylation levels. Acetylation of arginine kinase might be related to ATP production and interaction with symbiotic bacteria. Myosin heavy chain (Ama01085) has the most acetylation sites and might improve the actomyosin system stability through acetylation. Further validation is required for the acetylation modification from Vesicomyidae clams. CONCLUSION A novel comparative analysis was undertaken to investigate the acetylation of lysine in Vesicomyidae clams, yielding novel insights into the regulatory role of lysine acetylation in deep-sea organisms. The findings present many potential proteins for further exploration of acetylation functions in cold seep clams and other deep-sea mollusks.
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Affiliation(s)
- Xue Kong
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Wei Wang
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Sunan Chen
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Manzong Song
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Ying Zhi
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Yuefeng Cai
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China
| | - Haibin Zhang
- Institute of Deep-sea Science and Engineering, Chinese Academy of Sciences, Sanya, 572000, China
| | - Xin Shen
- School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, 222000, China.
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang, 222000, China.
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Hu Y, Zheng Y, Liu C, You Y, Wu Y, Wang P, Wu Y, Ba H, Lu J, Yuan Y, Liu P, Mao Y. Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation. Cell Rep 2024; 43:114839. [PMID: 39392752 DOI: 10.1016/j.celrep.2024.114839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 08/15/2024] [Accepted: 09/20/2024] [Indexed: 10/13/2024] Open
Abstract
Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitro and in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.
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Affiliation(s)
- Yuehuai Hu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Yongjia Zheng
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Cui Liu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Yuyu You
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Ying Wu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Panxia Wang
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Yiyang Wu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Hongjun Ba
- Department of Pediatric Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jing Lu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China
| | - Yanqiu Yuan
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
| | - Peiqing Liu
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
| | - Yang Mao
- School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
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20
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Liu YP, He B, Wang WX, Pan WL, Jiao L, Yan JJ, Sun SC, Zhang Y. PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation. Mitochondrion 2024; 78:101946. [PMID: 39147088 DOI: 10.1016/j.mito.2024.101946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
Mitochondria play dominant roles in various cellular processes such as energy production, apoptosis, calcium homeostasis, and oxidation-reduction balance. Maintaining mitochondrial quality through mitophagy is essential, especially as its impairment leads to the accumulation of dysfunctional mitochondria in aging oocytes. Our previous research revealed that PKD expression decreases in aging oocytes, and its inhibition negatively impacts oocyte quality. Given PKD's role in autophagy mechanisms, this study investigates whether PKD regulates mitophagy to maintain mitochondrial function and support oocyte maturation. When fully grown oocytes were treated with CID755673, a potent PKD inhibitor, we observed meiosis arrest at the metaphase I stage, along with decreased spindle stability. Our results demonstrate an association with mitochondrial dysfunction, including reduced ATP production and fluctuations in Ca2+ homeostasis, which ultimately lead to increased ROS accumulation, stimulating oxidative stress-induced apoptosis and DNA damage. Further research has revealed that these phenomena result from PKD inhibition, which affects the phosphorylation of ULK, thereby reducing autophagy levels. Additionally, PKD inhibition leads to decreased Parkin expression, which directly and negatively affects mitophagy. These defects result in the accumulation of damaged mitochondria in oocytes, which is the primary cause of mitochondrial dysfunction. Taken together, these findings suggest that PKD regulates mitophagy to support mitochondrial function and mouse oocyte maturation, offering insights into potential targets for improving oocyte quality and addressing mitochondrial-related diseases in aging females.
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Affiliation(s)
- Ya-Ping Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Bing He
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Wen-Xin Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Wen-Lin Pan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Le Jiao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Jing-Jing Yan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Shao-Chen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yu Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
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21
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Gao X, Pan T, Gao Y, Zhu W, Liu L, Duan W, Han C, Feng B, Yan W, Song Q, Liu Y, Yue L. Acetylation of PGK1 at lysine 323 promotes glycolysis, cell proliferation, and metastasis in luminal A breast cancer cells. BMC Cancer 2024; 24:1054. [PMID: 39192221 PMCID: PMC11348675 DOI: 10.1186/s12885-024-12792-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND In prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology. METHODS Acetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection. RESULTS Acetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin. CONCLUSION PGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy.
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Affiliation(s)
- Xiuli Gao
- Research Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Ting Pan
- Department of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Yu Gao
- The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Wenbin Zhu
- Research Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Likun Liu
- Research Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Wenbo Duan
- Department of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Cuicui Han
- College of Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Bo Feng
- Dean's Office, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Wenjing Yan
- College of Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Qiuhang Song
- College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yunlong Liu
- The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China.
| | - Liling Yue
- Research Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, China.
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22
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Sarmadi F, Gao Z, Su J, Barbier C, Artusa P, Bijian K, Gleason JL, White JH. Bifunctionality and Antitumor Efficacy of ZG-126, a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule. J Med Chem 2024; 67:11182-11196. [PMID: 38906533 PMCID: PMC11249012 DOI: 10.1021/acs.jmedchem.4c00706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2024]
Abstract
Analogues of hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signal through the nuclear vitamin D receptor (VDR). They have potential in combination therapies with other anticancer agents such as histone deacetylase inhibitors (HDACi's). Here, we characterize the ZG series of hybrid compounds that combine HDACi within the backbone of a VDR agonist. All display improved solubility, with ZG-126 being the most robustly bifunctional molecule in multiple cell lines. ZG-126 is well tolerated and strongly induces VDR target gene expression in vivo at therapeutic doses. Its antitumor efficacy is superior to 1,25D and the HDACi SAHA, separately or together, in mouse models of melanoma and triple-negative breast cancer (TNBC). Notably, ZG-126 treatment reduces metastases almost 4-fold in an aggressive TNBC model. ZG-126 also reduces total macrophage infiltration and the proportion of immunosuppressive M2-polarized macrophages in TNBC tumors by 2-fold. ZG-126 thus represents a bifunctional and efficacious anticancer agent with improved physicochemical properties.
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Affiliation(s)
- Fatemeh Sarmadi
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Zhizhong Gao
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada
| | - Jie Su
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada
| | - Camille Barbier
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Patricio Artusa
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Krikor Bijian
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada
| | - James L Gleason
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada
| | - John H White
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Department of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
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23
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Rizo J, Encarnación-Guevara S. Bacterial protein acetylation: mechanisms, functions, and methods for study. Front Cell Infect Microbiol 2024; 14:1408947. [PMID: 39027134 PMCID: PMC11254643 DOI: 10.3389/fcimb.2024.1408947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Lysine acetylation is an evolutionarily conserved protein modification that changes protein functions and plays an essential role in many cellular processes, such as central metabolism, transcriptional regulation, chemotaxis, and pathogen virulence. It can alter DNA binding, enzymatic activity, protein-protein interactions, protein stability, or protein localization. In prokaryotes, lysine acetylation occurs non-enzymatically and by the action of lysine acetyltransferases (KAT). In enzymatic acetylation, KAT transfers the acetyl group from acetyl-CoA (AcCoA) to the lysine side chain. In contrast, acetyl phosphate (AcP) is the acetyl donor of chemical acetylation. Regardless of the acetylation type, the removal of acetyl groups from acetyl lysines occurs only enzymatically by lysine deacetylases (KDAC). KATs are grouped into three main superfamilies based on their catalytic domain sequences and biochemical characteristics of catalysis. Specifically, members of the GNAT are found in eukaryotes and prokaryotes and have a core structural domain architecture. These enzymes can acetylate small molecules, metabolites, peptides, and proteins. This review presents current knowledge of acetylation mechanisms and functional implications in bacterial metabolism, pathogenicity, stress response, translation, and the emerging topic of protein acetylation in the gut microbiome. Additionally, the methods used to elucidate the biological significance of acetylation in bacteria, such as relative quantification and stoichiometry quantification, and the genetic code expansion tool (CGE), are reviewed.
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Affiliation(s)
| | - Sergio Encarnación-Guevara
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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24
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Borotto NB. The path forward for protein footprinting, covalent labeling, and mass spectrometry-based protein conformational analyses. JOURNAL OF MASS SPECTROMETRY : JMS 2024; 59:e5064. [PMID: 38873895 PMCID: PMC11210343 DOI: 10.1002/jms.5064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/15/2024]
Abstract
Mass spectrometry-based approaches to assess protein conformation have become widely utilized due to their sensitivity, low sample requirements, and broad applicability to proteins regardless of size and environment. Their wide applicability and sensitivity also make these techniques suitable for the analysis of complex mixtures of proteins, and thus, they have been applied at the cell and even the simple organism levels. These works are impressive, but they predominately employ "bottom-up" workflows and require proteolytic digestion prior to analysis. Once digested, it is not possible to distinguish the proteoform from which any single peptide is derived and therefore, one cannot associate distal-in primary structure-concurrent post-translational modifications (PTMs) or covalent labels, as they would be found on separate peptides. Thus, analyses via bottom-up proteomics report the average PTM status and higher-order structure (HOS) of all existing proteoforms. Second, these works predominately employ promiscuous reagents to probe protein HOS. While this does lead to improved conformational resolution, the formation of many products can divide the signal associated with low-copy number proteins below signal-to-noise thresholds and complicate the bioinformatic analysis of these already challenging systems. In this perspective, I further detail these limitations and discuss the positives and negatives of top-down proteomics as an alternative.
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25
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Ito M, Nishida Y, Iwamoto T, Kanai A, Aoyama S, Ueki K, Uzawa H, Iida H, Watada H. Protein acylations induced by a ketogenic diet demonstrate diverse patterns depending on organs and differ between histones and global proteins. Biochem Biophys Res Commun 2024; 712-713:149960. [PMID: 38640734 DOI: 10.1016/j.bbrc.2024.149960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
An essential ketone body, β-hydroxybutyrate (BOHB), plays various roles in physiological regulations via protein acylations such as lysine acetylation and β-hydroxybutyrylation. Here, to understand how BOHB systemically regulates acylations from an overarching perspective, we administered a ketogenic diet to mice to increase BOHB concentration and examined acylations. We found that global acetylation and β-hydroxybutyrylation dramatically increase in various organs except for the brains, where the increase was much smaller than in the other organs. Interestingly, we observe no increase in histone acetylation in the organs where significant global protein acetylation occurs despite a substantial rise in histone β-hydroxybutyrylation. Finally, we compared the transcriptome data of the mice's liver after the ketogenic diet to the public databases, showing that upregulated genes are enriched in those related to histone β-hydroxybutyrylation in starvation. Our data indicate that a ketogenic diet induces diverse patterns of acylations depending on organs and protein localizations, suggesting that different mechanisms regulate acylations and that the ketogenic diet is associated with starvation in terms of protein modifications.
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Affiliation(s)
- Minami Ito
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yuya Nishida
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Tatsuya Iwamoto
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Akiko Kanai
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Shuhei Aoyama
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Kyosei Ueki
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirotsugu Uzawa
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hitoshi Iida
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirotaka Watada
- Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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26
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Liebner T, Kilic S, Walter J, Aibara H, Narita T, Choudhary C. Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription. Nat Commun 2024; 15:4962. [PMID: 38862536 PMCID: PMC11166988 DOI: 10.1038/s41467-024-49370-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.
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Affiliation(s)
- Tim Liebner
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Sinan Kilic
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Jonas Walter
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Hitoshi Aibara
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Takeo Narita
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Chunaram Choudhary
- Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
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Sood V, Holewinski R, Andresson T, Larson DR, Misteli T. Identification of molecular determinants of gene-specific bursting patterns by high-throughput imaging screens. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.08.597999. [PMID: 38903099 PMCID: PMC11188098 DOI: 10.1101/2024.06.08.597999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Stochastic transcriptional bursting is a universal property of active genes. While different genes exhibit distinct bursting patterns, the molecular mechanisms for gene-specific stochastic bursting are largely unknown. We have developed and applied a high-throughput-imaging based screening strategy to identify cellular factors and molecular mechanisms that determine the bursting behavior of human genes. Focusing on epigenetic regulators, we find that protein acetylation is a strong acute modulator of burst frequency, burst size and heterogeneity of bursting. Acetylation globally affects the Off-time of genes but has gene-specific effects on the On-time. Yet, these effects are not strongly linked to promoter acetylation, which do not correlate with bursting properties, and forced promoter acetylation has variable effects on bursting. Instead, we demonstrate acetylation of the Integrator complex as a key determinant of gene bursting. Specifically, we find that elevated Integrator acetylation decreases bursting frequency. Taken together our results suggest a prominent role of non-histone proteins in determining gene bursting properties, and they identify histone-independent acetylation of a transcription cofactor as an allosteric modulator of bursting via a far-downstream bursting checkpoint.
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Affiliation(s)
- Varun Sood
- National Cancer Institute, Bethesda, MD, USA
| | - Ronald Holewinski
- Protein Characterization Laboratory, National Cancer Institute, Frederick, MD, USA
| | - Thorkell Andresson
- Protein Characterization Laboratory, National Cancer Institute, Frederick, MD, USA
| | | | - Tom Misteli
- National Cancer Institute, Bethesda, MD, USA
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Ren C, Li X, Li J, Huang X, Bai Y, Schroyen M, Hou C, Wang Z, Zhang D. Acetylation and Phosphorylation Regulate the Role of Pyruvate Kinase as a Glycolytic Enzyme or a Protein Kinase in Lamb. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:11724-11732. [PMID: 38718268 DOI: 10.1021/acs.jafc.4c00082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
Protein post-translational modifications (PTMs) play an essential role in meat quality development. However, the effect of specific PTM sites on meat proteins has not been investigated yet. The characteristics of pyruvate kinase M (PKM) were found to exhibit a close correlation with final meat quality, and thus, serine 99 (S99) and lysine 137 (K137) in PKM were mutated to study their effect on PKM function. The structural and functional properties of five lamb PKM variants, including wild-type PKM (wtPKM), PKM_S99D (S99 phosphorylation), PKM_S99A (PKM S99 dephosphorylation), PKM_K137Q (PKM K137 acetylation), and PKM_K137R (PKM K137 deacetylation), were evaluated. The results showed that the secondary structure, tertiary structure, and polymer formation were affected among different PKM variants. In addition, the glycolytic activity of PKM_K137Q was decreased because of its weakened binding with phosphoenolpyruvate. In the PKM_K137R variant, the actin phosphorylation level exhibited a decrease, suggesting a low kinase activity of PKM_K137R. The results of molecular simulation showed a 42% reduction in the interface area between PKM_K137R and actin, in contrast to wtPKM and actin. These findings are significant for revealing the mechanism of how PTMs regulate PKM function and provide a theoretical foundation for the development of precise meat quality preservation technology.
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Affiliation(s)
- Chi Ren
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
- Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Passage des Déportés 2, Gembloux 5030, Belgium
| | - Xin Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Juan Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Xiaolan Huang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Yuqiang Bai
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Martine Schroyen
- Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Passage des Déportés 2, Gembloux 5030, Belgium
| | - Chengli Hou
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Zhenyu Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
| | - Dequan Zhang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality & Safety in Harvest, Storage, Transportation, Management and Control, Ministry of Agriculture and Rural Affairs, Beijing 100193, P. R. China
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Hao B, Chen K, Zhai L, Liu M, Liu B, Tan M. Substrate and Functional Diversity of Protein Lysine Post-translational Modifications. GENOMICS, PROTEOMICS & BIOINFORMATICS 2024; 22:qzae019. [PMID: 38862432 PMCID: PMC12016574 DOI: 10.1093/gpbjnl/qzae019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 11/11/2023] [Accepted: 01/08/2024] [Indexed: 06/13/2024]
Abstract
Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.
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Affiliation(s)
- Bingbing Hao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Kaifeng Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Linhui Zhai
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China
| | - Muyin Liu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Bin Liu
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
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30
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Paluch KV, Platz KR, Rudisel EJ, Erdmann RR, Laurin TR, Dittenhafer-Reed KE. The role of lysine acetylation in the function of mitochondrial ribosomal protein L12. Proteins 2024; 92:583-592. [PMID: 38146092 DOI: 10.1002/prot.26654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/27/2023] [Accepted: 12/01/2023] [Indexed: 12/27/2023]
Abstract
Mitochondria play a central role in energy production and cellular metabolism. Mitochondria contain their own small genome (mitochondrial DNA, mtDNA) that carries the genetic instructions for proteins required for ATP synthesis. The mitochondrial proteome, including the mitochondrial transcriptional machinery, is subject to post-translational modifications (PTMs), including acetylation and phosphorylation. We set out to determine whether PTMs of proteins associated with mtDNA may provide a potential mechanism for the regulation of mitochondrial gene expression. Here, we focus on mitochondrial ribosomal protein L12 (MRPL12), which is thought to stabilize mitochondrial RNA polymerase (POLRMT) and promote transcription. Numerous acetylation sites of MRPL12 were identified by mass spectrometry. We employed amino acid mimics of the acetylated (lysine to glutamine mutants) and deacetylated (lysine to arginine mutants) versions of MRPL12 to interrogate the role of lysine acetylation in transcription initiation in vitro and mitochondrial gene expression in HeLa cells. MRPL12 acetyl and deacetyl protein mimics were purified and assessed for their ability to impact mtDNA promoter binding of POLRMT. We analyzed mtDNA content and mitochondrial transcript levels in HeLa cells upon overexpression of acetyl and deacetyl mimics of MRPL12. Our results suggest that MRPL12 single-site acetyl mimics do not change the mtDNA promoter binding ability of POLRMT or mtDNA content in HeLa cells. Individual acetyl mimics may have modest effects on mitochondrial transcript levels. We found that the mitochondrial deacetylase, Sirtuin 3, is capable of deacetylating MRPL12 in vitro, suggesting a potential role for dynamic acetylation controlling MRPL12 function in a role outside of the regulation of gene expression.
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Affiliation(s)
- Katelynn V Paluch
- Department of Chemistry and Biochemistry, Hope College, Holland, Michigan, USA
| | - Karlie R Platz
- Department of Chemistry and Biochemistry, Hope College, Holland, Michigan, USA
| | - Emma J Rudisel
- Department of Chemistry and Biochemistry, Hope College, Holland, Michigan, USA
| | - Ryan R Erdmann
- Department of Chemistry and Biochemistry, Hope College, Holland, Michigan, USA
| | - Taylor R Laurin
- Department of Chemistry and Biochemistry, Hope College, Holland, Michigan, USA
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Gong M, Zhang Y, Chen N, Ma LL, Feng XM, Yan YX. Proteomics in Cardiovascular disease. Clin Chim Acta 2024; 557:117877. [PMID: 38537675 DOI: 10.1016/j.cca.2024.117877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/14/2024] [Accepted: 03/14/2024] [Indexed: 04/13/2024]
Abstract
This study focuses on recent advances in proteomics and provides an up-to-date use of this technology in identifying cardiovascular disease (CVD) biomarkers. A total of eight electronic databases (PubMed, EMBASE, Web of Science, Cochrane Library, Wanfang, Vip, Sinomed, and CNKI) were searched and five were used for integrative analysis of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic ratio (DOR) and 1 secondary indicator area under the curve (AUC). This systematic review and integrative analysis summarized potential biomarkers previously identified by proteomics. The integrative analysis suggested that proteomics technology had high clinical value in CVD diagnosis. The findings provided new possible directions for the prevention or diagnosis of CVD.
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Affiliation(s)
- Miao Gong
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Yu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Ning Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Lin-Lin Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Xu-Man Feng
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Yu-Xiang Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China; Municipal Key Laboratory of Clinical Epidemiology, Beijing, China.
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32
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Zhou Z, Arroum T, Luo X, Kang R, Lee YJ, Tang D, Hüttemann M, Song X. Diverse functions of cytochrome c in cell death and disease. Cell Death Differ 2024; 31:387-404. [PMID: 38521844 PMCID: PMC11043370 DOI: 10.1038/s41418-024-01284-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024] Open
Abstract
The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.
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Affiliation(s)
- Zhuan Zhou
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Yong J Lee
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
| | - Xinxin Song
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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Fan S, Kong C, Zhou R, Zheng X, Ren D, Yin Z. Protein Post-Translational Modifications Based on Proteomics: A Potential Regulatory Role in Animal Science. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6077-6088. [PMID: 38501450 DOI: 10.1021/acs.jafc.3c08332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Genomic studies in animal breeding have provided a wide range of references; however, it is important to note that genes and mRNA alone do not fully capture the complexity of living organisms. Protein post-translational modification, which involves covalent modifications regulated by genetic and environmental factors, serves as a fundamental epigenetic mechanism that modulates protein structure, activity, and function. In this review, we comprehensively summarize various phosphorylation and acylation modifications on metabolic enzymes relevant to energy metabolism in animals, including acetylation, succinylation, crotonylation, β-hydroxybutylation, acetoacetylation, and lactylation. It is worth noting that research on animal energy metabolism and modification regulation lags behind the demands for growth and development in animal breeding compared to human studies. Therefore, this review provides a novel research perspective by exploring unreported types of modifications in livestock based on relevant findings from human or animal models.
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Affiliation(s)
- Shuhao Fan
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Chengcheng Kong
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230013, China
| | - Ren Zhou
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Xianrui Zheng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Dalong Ren
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Zongjun Yin
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
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Morse PT, Arroum T, Wan J, Pham L, Vaishnav A, Bell J, Pavelich L, Malek MH, Sanderson TH, Edwards BF, Hüttemann M. Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis. Cells 2024; 13:493. [PMID: 38534337 PMCID: PMC10969761 DOI: 10.3390/cells13060493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/07/2024] [Accepted: 03/09/2024] [Indexed: 03/28/2024] Open
Abstract
Cytochrome c (Cytc) has both life-sustaining and cellular death-related functions, depending on subcellular localization. Within mitochondria, Cytc acts as a single electron carrier as part of the electron transport chain (ETC). When released into the cytosol after cellular insult, Cytc triggers the assembly of the apoptosome, committing the cell to intrinsic apoptosis. Due to these dual natures, Cytc requires strong regulation by the cell, including post-translational modifications, such as phosphorylation and acetylation. Six phosphorylation sites and three acetylation sites have been detected on Cytc in vivo. Phosphorylations at T28, S47, Y48, T49, T58, and Y97 tend to be present under basal conditions in a tissue-specific manner. In contrast, the acetylations at K8, K39, and K53 tend to be present in specific pathophysiological conditions. All of the phosphorylation sites and two of the three acetylation sites partially inhibit respiration, which we propose serves to maintain an optimal, intermediate mitochondrial membrane potential (ΔΨm) to minimize reactive oxygen species (ROS) production. Cytc phosphorylations are lost during ischemia, which drives ETC hyperactivity and ΔΨm hyperpolarization, resulting in exponential ROS production thus causing reperfusion injury following ischemia. One of the acetylation sites, K39, shows a unique behavior in that it is gained during ischemia, stimulating respiration while blocking apoptosis, demonstrating that skeletal muscle, which is particularly resilient to ischemia-reperfusion injury compared to other organs, possesses a different metabolic strategy to handle ischemic stress. The regulation of Cytc by these post-translational modifications underscores the importance of Cytc for the ETC, ΔΨm, ROS production, apoptosis, and the cell as a whole.
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Affiliation(s)
- Paul T. Morse
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
| | - Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
| | - Junmei Wan
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
| | - Lucynda Pham
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
| | - Asmita Vaishnav
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA
| | - Jamie Bell
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
- Division of Pediatric Critical Care, Children’s Hospital of Michigan, Central Michigan University, Detroit, MI 48201, USA
| | - Lauren Pavelich
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA
| | - Moh H. Malek
- Department of Health Care Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Thomas H. Sanderson
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Brian F.P. Edwards
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; (P.T.M.)
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA
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Xie R, Zhang B, Tumukunde E, Zhuang Z, Yuan J, Wang S. Succinylated acetyl-CoA carboxylase contributes to aflatoxin biosynthesis, morphology development, and pathogenicity in Aspergillus flavus. Int J Food Microbiol 2024; 413:110585. [PMID: 38246023 DOI: 10.1016/j.ijfoodmicro.2024.110585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/23/2024]
Abstract
Acetyl-CoA carboxylase (ACC), which catalyzes acetyl-CoA to produce malonyl-CoA, is crucial for the synthesis of mycotoxins, ergosterol, and fatty acids in various genera. However, its biofunction in Aspergillus flavus has not been reported. In this study, the accA gene was deleted and site-mutated to explore the influence of ACC on sporulation, sclerotium formation, and aflatoxin B1 (AFB1) biosynthesis. The results revealed that ACC positively regulated conidiation and sclerotium formation, but negatively regulated AFB1 production. In addition, we found that ACC is a succinylated protein, and mutation of lysine at position 990 of ACC to glutamic acid or arginine (accAK990E or accAK990R) changed the succinylation level of ACC. The accAK990E and accAK990R mutations (to imitate the succinylation and desuccinylation at K990 of ACC, respectively) downregulated fungal conidiation and sclerotium formation while increasing AFB1 production, revealing that the K990 is an important site for ACC's biofunction. These results provide valuable perspectives for future mechanism studies of the emerging roles of succinylated ACC in the regulation of the A. flavus phenotype, which is advantageous for the prevention and control of A. flavus hazards.
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Affiliation(s)
- Rui Xie
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China
| | - Bei Zhang
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China
| | - Elisabeth Tumukunde
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China
| | - Zhenhong Zhuang
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China
| | - Jun Yuan
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China
| | - Shihua Wang
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry University, 350002 Fuzhou, China.
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Li Y, Pan B, Zhang F, Jia X, Zhu X, Tong X, Zhao J, Li C. TPI1 promotes MAPK/ERK-induced EMT, cell migration and invasion in lung adenocarcinoma. Thorac Cancer 2024; 15:327-338. [PMID: 38130074 PMCID: PMC10834191 DOI: 10.1111/1759-7714.15196] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Triosephosphate isomerase 1 (TPI1), as a widely involved glycolytic enzyme, plays a significant role in glucose metabolism and is highly expressed in various tumors. However, its role in lung adenocarcinoma (LUAD) remains incompletely understood. METHODS Through bioinformatic analysis, we identified a positive association between high expression of TPI1 and metastasis in LUAD. Western blot, RT-qPCR, wound healing assays and transwell experiments, were employed to investigate potential mechanisms. RESULTS In this study, bioinformatic analysis showed that high expression of TPI1 was associated with poor prognosis in LUAD patients. We examined the expression of TPI1 in 29 paired LUAD tissues and found that TPI1 expression was higher in LUAD tissues than in paired adjacent noncancerous tissues. Meanwhile, overexpression of TPI1 promoted the epithelial-mesenchymal transition (EMT) process in LUAD cells, while silencing TPI1 weakened the EMT process. Furthermore, TPI1 was shown to regulate EMT through the MAPK/ERK signaling pathway. CONCLUSION TPI1 promotes LUAD metastasis by activating the MAPK/ERK signaling pathway.
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Affiliation(s)
- Yu Li
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Bin Pan
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of Cardiothoracic SurgeryPeople's Hospital Affiliated to Jiangsu UniversityZhenjiangChina
| | | | - Xinyu Jia
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xinyu Zhu
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xin Tong
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Jun Zhao
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Chang Li
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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Zhang J, Li W, Xue S, Gao P, Wang H, Chen H, Hong Y, Sun Q, Lu L, Wang Y, Wang Q. Qishen granule attenuates doxorubicin-induced cardiotoxicity by protecting mitochondrial function and reducing oxidative stress through regulation of Sirtuin3. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117134. [PMID: 37714227 DOI: 10.1016/j.jep.2023.117134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Doxorubicin (DOX) is one of the most potent chemotherapy drugs available today. However, the adverse effect of cardiotoxicity limits its clinical application. New approaches are being investigated for the treatment of doxorubicin-induced cardiotoxicity (DIC). Doxorubicin is enriched in mitochondria and it could induce imbalance of protein modification, including acetylation of mitochondria proteins, thereby inducing DIC. Restoration of mitochondria function is an effective way to attenuate DIC. The formula for traditional Chinese medicine Granules of Qishen (QSG) was derived from the classic formula "Zhen-Wu-Tang" which has been extensively used in the treatment of myocardial infarction. It consists of six traditional Chinese medicines, including Astragalus membranaceus var. mongholicus (Bunge) P.K.Hsiao (Fabaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Lonicera japonica Thunb. (Caprifoliaceae), Aconitum carmichaelii Debeaux (Ranunculaceae), Scrophularia ningpoensis Hemsl. (Scrophulariaceae), and Glycyrrhiza uralensis Fisch. (Fabaceae). QSG is a potential anti-DIC formula. A better understanding of the effectiveness and pharmacological mechanisms of QSG will aid in the prevention and treatment of DIC. AIM OF THE STUDY The purpose of this research was to explore the effectiveness of QSG in the treatment of DIC and to explore whether QSG could protect mitochondrial function and reduce oxidative damage by activating Sirtuin3(SIRT3)/Acetylated-superoxide dismutase 2(Ac-SOD2) signaling pathway. MATERIALS AND METHODS DOX was injected into mice through the tail vein to construct a mouse model of DOX-induced cardiotoxicity to explore the therapeutic effect of QSG in animals. Meanwhile, the H9C2 cell model was used to study the mechanism of QSG. The cardiac function was evaluated by echocardiography, hematoxylin-eosin (H&E) staining and measurement of serum levels of creatine kinase isoenzymes (CK-MB) and lactate dehydrogenase (LDH). Oxidative damage was evaluated by 2',7'-dichlorodihydro fluorescein diacetate (DCFH-DA) staining and Mito-SOX Red staining. Levels of total superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured by following the instructions of commercially available kits. In order to detect the changes in mitochondrial membrane potential, cells were stained using the mitochondrial membrane potential detection kit (JC-1). Western blot analysis was applied to detect protein expressions of SIRT3, Ac-SOD2, Acetylation Lysine (Ac-Lys), Bax and Bcl-2. H9C2 cells were treated with SIRT3 inhibitor, in order to determine if QSG had effects via the SIRT3/Ac-SOD2 pathway. RESULTS In vivo studies showed that QSG ameliorated doxorubicin-induced damage of cardiac function in DIC mice model. The ejection fraction (EF) and fractional shortening (FS) were all up-regulated by QSG treatment. QSG decreased MDA levels and increased SOD activity. Meanwhile, doxorubicin induced high level of protein acetylation and QSG restored the acetylated protein back to normal levels. In particular, QSG upregulated expression of SIRT3 and downregulated Ac-SOD level. In vitro study demonstrated that QSG restored mitochondrial membrane potential, increased ATP level and reduced mitochondrial ROS production. When H9C2 cells were co-incubated with SIRT3 inhibitor, the efficacies of QSG on mitochondrial function were abrogated. Meanwhile, the regulative effects of QSG on SIRT3/Ac-SOD2 pathway were also abolished. CONCLUSION This study demonstrates that QSG is effective in treating DIC. QSG ameliorates oxidative damage and protects mitochondrial function partly by restoring protein acetylation level and by activating the SIRT3/Ac-SOD2 pathway.
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Affiliation(s)
- Jingmei Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Weili Li
- College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Siming Xue
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Pengrong Gao
- College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Hui Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Huan Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yiqin Hong
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qianbin Sun
- College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Linghui Lu
- College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; Beijing Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, 100029, China.
| | - Yong Wang
- College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; Beijing Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, 100029, China.
| | - Qiyan Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China; Beijing Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, 100029, China.
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Liu Y, Wei H, Li J. A review on SIRT3 and its natural small molecule activators as a potential Preventive and therapeutic target. Eur J Pharmacol 2024; 963:176155. [PMID: 37914065 DOI: 10.1016/j.ejphar.2023.176155] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/03/2023]
Abstract
Sirtuins (SIRTs) were originally characterized by yeast Sir2 as a lifespan regulator that is conserved in all three structural domains of bacteria, archaea and eukaryotes and belong to histone deacetylases consisting of seven members (SIRT1-SIRT7). Surprisingly, SIRTs have been shown to play important regulatory roles in almost all cellular functions, including mitochondrial biogenesis, oxidative stress, inflammation, cell growth, energy metabolism, neural function, and stress resistance. Among the SIRT members, sirtuin 3 (SIRT3) is one of the most important deacetylases that regulates the mitochondrial acetylation and plays a role in pathological processes, such as metabolism, DNA repair, oxidative stress, apoptosis and ferroptosis. Therefore, SIRT3 is considered as a potential target for the treatment of a variety of pathological diseases, including metabolic diseases, neurodegenerative diseases, age-related diseases and others. Furthermore, the isolation, screening, and development of SIRT3 signaling agonists, especially from natural products, have become a widely investigated objective. This paper describes the structure of SIRT3 protein, discusses the pathological process of SIRT3-mediated acetylation modification, and reviews the role of SIRT3 in diseases, SIRT3 activators and its related disease studies.
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Affiliation(s)
- Yuanyuan Liu
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Haidong Wei
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
| | - Jianhong Li
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China; Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin, 150030, China.
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Gong Y, Dai L. Decoding Ubiquitin Modifications by Mass Spectrometry. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1466:1-18. [PMID: 39546132 DOI: 10.1007/978-981-97-7288-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Protein ubiquitination is a critical and widely distributed post-translational modification (PTM) involved in the regulation of almost every cellular process and pathway in cells, such as proteostasis, DNA repair, trafficking, and immunity. Mass spectrometry (MS)-based proteomics is a robust tool to decode the complexity of ubiquitin networks by disclosing the proteome-wide ubiquitination sites, the length, linkage and topology of ubiquitin chains, the chemical modification of ubiquitin chains, and the crosstalk between ubiquitination and other PTMs. In this chapter, we discuss the application of MS in the interpretation of the ubiquitin code.
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Affiliation(s)
- Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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Zhang M, Luo X, Zhang B, Luo D, Huang L, Long Q. Unveiling OSCP as the potential therapeutic target for mitochondrial dysfunction-related diseases. Life Sci 2024; 336:122293. [PMID: 38030056 DOI: 10.1016/j.lfs.2023.122293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/06/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.
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Affiliation(s)
- Mingyue Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xia Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Binzhi Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Lizhen Huang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qinqiang Long
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Baker ZN, Forny P, Pagliarini DJ. Mitochondrial proteome research: the road ahead. Nat Rev Mol Cell Biol 2024; 25:65-82. [PMID: 37773518 PMCID: PMC11378943 DOI: 10.1038/s41580-023-00650-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 10/01/2023]
Abstract
Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.
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Affiliation(s)
- Zakery N Baker
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Patrick Forny
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - David J Pagliarini
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
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Deng Z, He M, Hu H, Zhang W, Zhang Y, Ge Y, Ma T, Wu J, Li L, Sun M, An S, Li J, Huang Q, Gong S, Zhang J, Chen Z, Zeng Z. Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation. Autophagy 2024; 20:151-165. [PMID: 37651673 PMCID: PMC10761103 DOI: 10.1080/15548627.2023.2252265] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023] Open
Abstract
ABBREVIATIONS AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.
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Affiliation(s)
- Zhiya Deng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Man He
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongbin Hu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenqian Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yaoyuan Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yue Ge
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Nursing, Southern Medical University, Guangzhou, Guangdong, China
| | - Tongtong Ma
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Wu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lulan Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Maomao Sun
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Sheng An
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaxin Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiaobing Huang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Shenhai Gong
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jiaxing Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongqing Chen
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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Jiao L, Hu CX, Zhang Y, Zhang YX, Cai WW, Pan WL, Sun SC, Zhang Y. SIRT3 Regulates Levels of Deacetylated SOD2 to Prevent Oxidative Stress and Mitochondrial Dysfunction During Oocyte Maturation in Pigs. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2023; 29:2149-2160. [PMID: 37967302 DOI: 10.1093/micmic/ozad127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/12/2023] [Accepted: 10/23/2023] [Indexed: 11/17/2023]
Abstract
Mammalian oocyte maturation relies on mitochondrial ATP production, but this can lead to damaging reactive oxygen species (ROS). SIRT3, a mitochondrial sirtuin, plays a critical role in regulating mitochondrial redox balance in mouse oocytes under stress; however, its specific roles in porcine oocytes remain unclear. In this study, we utilized the SIRT3 inhibitor 3-TYP to investigate SIRT3's importance in porcine oocyte maturation. Our findings revealed that SIRT3 is expressed in porcine oocytes and its inhibition leads to maturation failure. This was evident through reduced polar body extrusion, arrested cell cycle, as well as disrupted spindle organization and actin distribution. Furthermore, SIRT3 inhibition resulted in a decrease in mitochondrial DNA copy numbers, disruption of mitochondrial membrane potential, and reduced ATP levels, all indicating impaired mitochondrial function in porcine oocytes. Additionally, the primary source of damaged mitochondria was associated with decreased levels of deacetylated superoxide dismutase 2 (SOD2) after SIRT3 inhibition, which led to ROS accumulation and oxidative stress-induced apoptosis. Taken together, our results suggest that SIRT3 regulates the levels of deacetylated SOD2 to maintain redox balance and preserve mitochondrial function during porcine oocyte maturation, with potential implications for improving pig reproduction.
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Affiliation(s)
- Le Jiao
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Chen-Xi Hu
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Yue Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Ying-Xin Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Wen-Wu Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Wen-Lin Pan
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Shao-Chen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
| | - Yu Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, China
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Goyal S, Cambronne XA. Layered mechanisms regulating the human mitochondrial NAD+ transporter SLC25A51. Biochem Soc Trans 2023; 51:1989-2004. [PMID: 38108469 PMCID: PMC10802112 DOI: 10.1042/bst20220318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/28/2023] [Accepted: 12/08/2023] [Indexed: 12/19/2023]
Abstract
SLC25A51 is the primary mitochondrial NAD+ transporter in humans and controls many local reactions by mediating the influx of oxidized NAD+. Intriguingly, SLC25A51 lacks several key features compared with other members in the mitochondrial carrier family, thus its molecular mechanism has been unclear. A deeper understanding would shed light on the control of cellular respiration, the citric acid cycle, and free NAD+ concentrations in mammalian mitochondria. This review discusses recent insights into the transport mechanism of SLC25A51, and in the process highlights a multitiered regulation that governs NAD+ transport. The aspects regulating SLC25A51 import activity can be categorized as contributions from (1) structural characteristics of the transporter itself, (2) its microenvironment, and (3) distinctive properties of the transported ligand. These unique mechanisms further evoke compelling new ideas for modulating the activity of this transporter, as well as new mechanistic models for the mitochondrial carrier family.
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Affiliation(s)
- Shivansh Goyal
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712
| | - Xiaolu A. Cambronne
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712
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Sung E, Sim H, Cho YC, Lee W, Bae JS, Tan M, Lee S. Global Profiling of Lysine Acetylation and Lactylation in Kupffer Cells. J Proteome Res 2023; 22:3683-3691. [PMID: 37897433 DOI: 10.1021/acs.jproteome.3c00156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2023]
Abstract
Among the various cell types that constitute the liver, Kupffer cells (KCs) are responsible for the elimination of gut-derived foreign products. Protein lysine acetylation (Kac) and lactylation (Kla) are dynamic and reversible post-translational modifications, and various global acylome studies have been conducted for liver and liver-derived cells. However, no such studies have been conducted on KCs. In this study, we identified 2198 Kac sites in 925 acetylated proteins and 289 Kla sites in 181 lactylated proteins in immortalized mouse KCs using global acylome technology. The subcellular distributions of proteins with Kac and Kla site modifications differed. Similarly, the specific sequence motifs surrounding acetylated or lactylated lysine residues also showed differences. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to better understand the differentially expressed proteins in the studies by Kac and Kla. In the newly identified Kla, we found K82 lactylation in the high-mobility group box-1 protein in the neutrophil extracellular trap formation category using KEGG enrichment analyses. Here, we report the first proteomic survey of Kac and Kla in KCs.
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Affiliation(s)
- Eunji Sung
- College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Hyunchae Sim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Young-Chang Cho
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Wonhwa Lee
- Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jong-Sup Bae
- College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Minjia Tan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Sangkyu Lee
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
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Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, Lou G, Yang C. Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy. Signal Transduct Target Ther 2023; 8:420. [PMID: 37926722 PMCID: PMC10625992 DOI: 10.1038/s41392-023-01647-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/23/2023] [Accepted: 09/12/2023] [Indexed: 11/07/2023] Open
Abstract
BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.
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Affiliation(s)
- Zhi-Qiang Wang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Zhao-Cong Zhang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Yu-Yang Wu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ya-Nan Pi
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Sheng-Han Lou
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tian-Bo Liu
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Ge Lou
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
| | - Chang Yang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
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Cao K, Xu J, Cao W, Wang X, Lv W, Zeng M, Zou X, Liu J, Feng Z. Assembly of mitochondrial succinate dehydrogenase in human health and disease. Free Radic Biol Med 2023; 207:247-259. [PMID: 37490987 DOI: 10.1016/j.freeradbiomed.2023.07.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/27/2023]
Abstract
Mitochondrial succinate dehydrogenase (SDH), also known as electron transport chain (ETC) Complex II, is the only enzyme complex engaged in both oxidative phosphorylation and the tricarboxylic acid (TCA) cycle. SDH has received increasing attention due to its crucial role in regulating mitochondrial metabolism and human health. Despite having the fewest subunits among the four ETC complexes, functional SDH is formed via a sequential and well-coordinated assembly of subunits. Along with the discovery of subunit-specific assembly factors, the dynamic involvement of the SDH assembly process in a broad range of diseases has been revealed. Recently, we reported that perturbation of SDH assembly in different tissues leads to interesting and distinct pathophysiological changes in mice, indicating a need to understand the intricate SDH assembly process in human health and diseases. Thus, in this review, we summarize recent findings on SDH pathogenesis with respect to disease and a focus on SDH assembly.
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Affiliation(s)
- Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China; Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Jie Xu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Wenli Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Xueqiang Wang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China
| | - Weiqiang Lv
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China
| | - Mengqi Zeng
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China
| | - Xuan Zou
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China.
| | - Zhihui Feng
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China.
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Yayli G, Bernardini A, Mendoza Sanchez PK, Scheer E, Damilot M, Essabri K, Morlet B, Negroni L, Vincent SD, Timmers HTM, Tora L. ATAC and SAGA co-activator complexes utilize co-translational assembly, but their cellular localization properties and functions are distinct. Cell Rep 2023; 42:113099. [PMID: 37682711 PMCID: PMC10591836 DOI: 10.1016/j.celrep.2023.113099] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 06/19/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
To understand the function of multisubunit complexes, it is of key importance to uncover the precise mechanisms that guide their assembly. Nascent proteins can find and bind their interaction partners during their translation, leading to co-translational assembly. Here, we demonstrate that the core modules of ATAC (ADA-two-A-containing) and SAGA (Spt-Ada-Gcn5-acetyltransferase), two lysine acetyl transferase-containing transcription co-activator complexes, assemble co-translationally in the cytoplasm of mammalian cells. In addition, a SAGA complex containing all of its modules forms in the cytoplasm and acetylates non-histone proteins. In contrast, ATAC complex subunits cannot be detected in the cytoplasm of mammalian cells. However, an endogenous ATAC complex containing two functional modules forms and functions in the nucleus. Thus, the two related co-activators, ATAC and SAGA, assemble using co-translational pathways, but their subcellular localization, cytoplasmic abundance, and functions are distinct.
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Affiliation(s)
- Gizem Yayli
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Andrea Bernardini
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Paulina Karen Mendoza Sanchez
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Freiburg, Germany; Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany
| | - Elisabeth Scheer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Mylène Damilot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Karim Essabri
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Bastien Morlet
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Luc Negroni
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - Stéphane D Vincent
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France
| | - H T Marc Timmers
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Freiburg, Germany; Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany
| | - László Tora
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France.
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Toro TB, Skripnikova EV, Bornes KE, Zhang K, Watt TJ. Endogenous expression of inactive lysine deacetylases reveals deacetylation-dependent cellular mechanisms. PLoS One 2023; 18:e0291779. [PMID: 37721967 PMCID: PMC10506724 DOI: 10.1371/journal.pone.0291779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/05/2023] [Indexed: 09/20/2023] Open
Abstract
Acetylation of lysine residues is an important and common post-translational regulatory mechanism occurring on thousands of non-histone proteins. Lysine deacetylases (KDACs or HDACs) are a family of enzymes responsible for removing acetylation. To identify the biological mechanisms regulated by individual KDACs, we created HT1080 cell lines containing chromosomal point mutations, which endogenously express either KDAC6 or KDAC8 having single inactivated catalytic domain. Engineered HT1080 cells expressing inactive KDA6 or KDAC8 domains remained viable and exhibited enhanced acetylation on known substrate proteins. RNA-seq analysis revealed that many changes in gene expression were observed when KDACs were inactivated, and that these gene sets differed significantly from knockdown and knockout cell lines. Using GO ontology, we identified several critical biological processes associated specifically with catalytic activity and others attributable to non-catalytic interactions. Treatment of wild-type cells with KDAC-specific inhibitors Tubastatin A and PCI-34051 resulted in gene expression changes distinct from those of the engineered cell lines, validating this approach as a tool for evaluating in-cell inhibitor specificity and identifying off-target effects of KDAC inhibitors. Probing the functions of specific KDAC domains using these cell lines is not equivalent to doing so using previously existing methods and provides novel insight into the catalytic functions of individual KDACs by investigating the molecular and cellular changes upon genetic inactivation.
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Affiliation(s)
- Tasha B. Toro
- Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, United States of America
| | - Elena V. Skripnikova
- Division of Basic and Pharmaceutical Sciences, Xavier University of Louisiana, New Orleans, LA, United States of America
| | - Kiara E. Bornes
- Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, United States of America
| | - Kun Zhang
- Department of Computer Science, Xavier University of Louisiana, New Orleans, LA, United States of America
- Bioinformatics Core, Xavier University of Louisiana, New Orleans, LA, United States of America
| | - Terry J. Watt
- Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, United States of America
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Gong Z, Qu Z, Yu Z, Li J, Liu B, Ma X, Cai J. Label-free quantitative detection and comparative analysis of lysine acetylation during the different life stages of Eimeria tenella. J Proteome Res 2023; 22:2785-2802. [PMID: 37562054 DOI: 10.1021/acs.jproteome.2c00726] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Proteome-wide lysine acetylation has been documented in apicomplexan parasite Toxoplasma gondii and Plasmodium falciparum. Here, we conducted the first lysine acetylome in unsporulated oocysts (USO), sporulated 7 h oocysts (SO 7h), sporulated oocysts (SO), sporozoites (S), and the second generation merozoites (SMG) of Eimeria tenella through a 4D label-free quantitative technique. Altogether, 8532 lysine acetylation sites on 2325 proteins were identified in E. tenella, among which 5445 sites on 1493 proteins were quantified. In addition, 557, 339, 478, 248, 241, and 424 differentially expressed proteins were identified in the comparisons SO7h vs USO, SO vs SO7h, SO vs USO, S vs SO, SMG vs S, and USO vs SMG, respectively. The bioinformatics analysis of the acetylome showed that the lysine acetylation is widespread on proteins of diverse functions. Moreover, the dynamic changes of lysine acetylome among E. tenella different life stages revealed significant regulation during the whole process of E. tenella growth and stage conversion. This study provides a beginning for the investigation of the regulate role of lysine acetylation in E. tenella and may provide new strategies for anticoccidiosis drug and vaccine development. Raw data are publicly available at iProX with the data set identifier PXD040368.
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Affiliation(s)
| | - Zigang Qu
- State Key Laboratory of Veterinary Etiological Biology; Key Laboratory of Veterinary Parasitology of Gansu Province; Innovation of Research Program of Gastrointestinal Infection and Mucosal Immunity of Poultry and Pig; Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province 225009, People's Republic of China
| | - Zhengqing Yu
- College of Animal Science and Technology, Ningxia University, Yinchuan, Ningxia Province 750021, People's Republic of China
| | - Jidong Li
- College of Animal Science and Technology, Ningxia University, Yinchuan, Ningxia Province 750021, People's Republic of China
| | - Baohong Liu
- State Key Laboratory of Veterinary Etiological Biology; Key Laboratory of Veterinary Parasitology of Gansu Province; Innovation of Research Program of Gastrointestinal Infection and Mucosal Immunity of Poultry and Pig; Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province 225009, People's Republic of China
| | - Xueting Ma
- State Key Laboratory of Veterinary Etiological Biology; Key Laboratory of Veterinary Parasitology of Gansu Province; Innovation of Research Program of Gastrointestinal Infection and Mucosal Immunity of Poultry and Pig; Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province 225009, People's Republic of China
| | - Jianping Cai
- State Key Laboratory of Veterinary Etiological Biology; Key Laboratory of Veterinary Parasitology of Gansu Province; Innovation of Research Program of Gastrointestinal Infection and Mucosal Immunity of Poultry and Pig; Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province 225009, People's Republic of China
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