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1
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Calderon-Rivera A, Gomez K, Rodríguez-Palma EJ, Khanna R. SUMOylation and DeSUMOylation: Tug of War of Pain Signaling. Mol Neurobiol 2025; 62:3305-3321. [PMID: 39276308 DOI: 10.1007/s12035-024-04478-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: 05/31/2024] [Accepted: 09/02/2024] [Indexed: 09/16/2024]
Abstract
SUMOylation is a post-translational modification that attaches a small ubiquitin-like modifier (SUMO) group to a target protein via SUMO ligases, while deSUMOylation refers to the removal of this SUMO group by sentrin-specific proteases (SENPs). Although the functions of these processes have been well described in the nucleus, the role of SUMOylation and deSUMOylation in regulating ion channels is emerging as a novel area of study. Despite this, their contributions to pain signaling remain less clear. Therefore, this review consolidates the current evidence on the link(s) between SUMOylation, deSUMOylation, and pain, with a specific focus on ion channels expressed in the sensory system. Additionally, we explore the role of SUMOylation in the expression and function of kinases, vesicle proteins, and transcription factors, which result in the modulation of certain ion channels contributing to pain. Altogether, this review aims to highlight the relationship between SUMOylation and deSUMOylation in the modulation of ion channels, ultimately exploring the potential therapeutic role of these processes in chronic pain.
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Affiliation(s)
- Aida Calderon-Rivera
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL, 32610, USA
| | - Kimberly Gomez
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL, 32610, USA
| | - Erick J Rodríguez-Palma
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL, 32610, USA
| | - Rajesh Khanna
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL, 32610, USA.
- Pain and Addiction Therapeutics (PATH) Collaboratory, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
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2
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Park JB, Lee MY, Lee J, Moon GH, Kim SJ, Chun YS. Neddylation steers the fate of cellular receptors. Exp Mol Med 2024; 56:2569-2577. [PMID: 39623094 DOI: 10.1038/s12276-024-01358-0] [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: 05/14/2024] [Revised: 09/05/2024] [Accepted: 09/18/2024] [Indexed: 12/28/2024] Open
Abstract
Cellular receptors regulate physiological responses by interacting with ligands, thus playing a crucial role in intercellular communication. Receptors are categorized on the basis of their location and engage in diverse biochemical mechanisms, which include posttranslational modifications (PTMs). Considering the broad impact and diversity of PTMs on cellular functions, we focus narrowly on neddylation, a modification closely resembling ubiquitination. We systematically organize its canonical and noncanonical roles in modulating proteins associated with cellular receptors with the goal of providing a more detailed perspective on the intricacies of both intracellular and cell-surface receptors.
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Affiliation(s)
- Jun Bum Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Min Young Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jooseung Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Geon Ho Moon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Joon Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yang-Sook Chun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
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3
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Jiaerken B, Liu W, Zheng J, Qu W, Wu Q, Ai Z. The SUMO Family: Mechanisms and Implications in Thyroid Cancer Pathogenesis and Therapy. Biomedicines 2024; 12:2408. [PMID: 39457720 PMCID: PMC11505470 DOI: 10.3390/biomedicines12102408] [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: 09/05/2024] [Revised: 10/12/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: Small ubiquitin-like modifiers (SUMOs) are pivotal in post-translational modifications, influencing various cellular processes, such as protein localization, stability, and genome integrity. (2) Methods: This review explores the SUMO family, including its isoforms and catalytic cycle, highlighting their significance in regulating key biological functions in thyroid cancer. We discuss the multifaceted roles of SUMOylation in DNA repair mechanisms, protein stability, and the modulation of receptor activities, particularly in the context of thyroid cancer. (3) Results: The aberrant SUMOylation machinery contributes to tumorigenesis through altered gene expression and immune evasion mechanisms. Furthermore, we examine the therapeutic potential of targeting SUMOylation pathways in thyroid cancer treatment, emphasizing the need for further research to develop effective SUMOylation inhibitors. (4) Conclusions: By understanding the intricate roles of SUMOylation in cancer biology, we can pave the way for innovative therapeutic strategies to improve outcomes for patients with advanced tumors.
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Affiliation(s)
- Bahejuan Jiaerken
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Wei Liu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jiaojiao Zheng
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Weifeng Qu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qiao Wu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhilong Ai
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
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4
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Wang J, Zhang R, Wu C, Wang L, Liu P, Li P. Exploring potential targets for natural product therapy of DN: the role of SUMOylation. Front Pharmacol 2024; 15:1432724. [PMID: 39431155 PMCID: PMC11486755 DOI: 10.3389/fphar.2024.1432724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 09/20/2024] [Indexed: 10/22/2024] Open
Abstract
Diabetic nephropathy (DN) is a common and serious micro-vascular complication of diabetes and a leading cause of end-stage renal disease globally. This disease primarily affects middle-aged and elderly individuals, especially those with a diabetes history of over 10 years and poor long-term blood glucose control. Small ubiquitin-related modifiers (SUMOs) are a group of reversible post-translational modifications of proteins that are widely expressed in eukaryotes. SUMO proteins intervene in the progression of DN by modulating various signaling cascades, such as Nrf2-mediated oxidative stress, NF-κB, TGF-β, and MAPK pathways. Recent advancements indicate that natural products regulating SUMOylation hold promise as targets for intervening in DN. In a previous article published in 2022, we reviewed the mechanisms by which SUMOylation intervenes in renal fibrosis and presented a summary of some natural products with therapeutic potential. Therefore, this paper will focus on DN. The aim of this review is to elucidate the mechanism of action of SUMOylation in DN and related natural products with therapeutic potential, thereby summarising the targets and candidate natural products for the treatment of DN through the modulation of SUMOylation, such as ginkgolic acid, ginkgolide B, resveratrol, astragaloside IV, etc., and highlighting that natural product-mediated modulation of SUMOylation is a potential therapeutic strategy for the treatment of DN as a potential therapeutic strategy.
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Affiliation(s)
- Jingjing Wang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Rui Zhang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Chenguang Wu
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Lifan Wang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Beijing, China
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5
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Zhuang Y, Fischer JB, Nishanth G, Schlüter D. Cross-regulation of Listeria monocytogenes and the host ubiquitin system in listeriosis. Eur J Cell Biol 2024; 103:151401. [PMID: 38442571 DOI: 10.1016/j.ejcb.2024.151401] [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: 09/10/2023] [Revised: 01/30/2024] [Accepted: 02/27/2024] [Indexed: 03/07/2024] Open
Abstract
The facultative intracellular bacterium Listeria (L.) monocytogenes may cause severe diseases in humans and animals. The control of listeriosis/L. monocytogenes requires the concerted action of cells of the innate and adaptive immune systems. In this regard, cell-intrinsic immunity of infected cells, activated by the immune responses, is crucial for the control and elimination intracellular L. monocytogenes. Both the immune response against L. monocytogenes and cell intrinsic pathogen control are critically regulated by post-translational modifications exerted by the host ubiquitin system and ubiquitin-like modifiers (Ubls). In this review, we discuss our current understanding of the role of the ubiquitin system and Ubls in listeriosis, as well as future directions of research.
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Affiliation(s)
- Yuan Zhuang
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover 30625, Germany.
| | - Johanna B Fischer
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover 30625, Germany
| | - Gopala Nishanth
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover 30625, Germany
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover 30625, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
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6
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Park SLL, Ramírez-Jarquín UN, Shahani N, Rivera O, Sharma M, Joshi PS, Hansalia A, Dagar S, McManus FP, Thibault P, Subramaniam S. SUMO modifies GβL and mediates mTOR signaling. J Biol Chem 2024; 300:105778. [PMID: 38395307 PMCID: PMC10982569 DOI: 10.1016/j.jbc.2024.105778] [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: 09/08/2023] [Revised: 01/25/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications; however, underlying mechanisms remain unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GβL (G protein β-subunit-like protein, also known as mLST8), is modified by SUMO1, 2, and 3 isoforms. Using mutagenesis and mass spectrometry, we identified that GβL is SUMOylated at lysine sites K86, K215, K245, K261, and K305. We found that SUMO depletion reduces mTOR-Raptor (regulatory protein associated with mTOR) and mTOR-Rictor (rapamycin-insensitive companion of mTOR) complex formation and diminishes nutrient-induced mTOR signaling. Reconstitution with WT GβL but not SUMOylation-defective KR mutant GβL promotes mTOR signaling in GβL-depleted cells. Taken together, we report for the very first time that SUMO modifies GβL, influences the assembly of mTOR protein complexes, and regulates mTOR activity.
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Affiliation(s)
| | | | - Neelam Shahani
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA
| | - Oscar Rivera
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA
| | - Manish Sharma
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA
| | | | - Aayushi Hansalia
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA
| | - Sunayana Dagar
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA
| | - Francis P McManus
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Chemistry, Université de Montréal, Montréal, Quebec, Canada
| | - Srinivasa Subramaniam
- Department of Neuroscience, The Wertheim UF Scripps Institute, Jupiter, Florida, USA; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, California, USA; Norman Fixel Institute for Neurological Diseases, Gainesville, Florida, USA.
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7
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Palacios A, Acharya P, Peidl A, Beck M, Blanco E, Mishra A, Bawa-Khalfe T, Pakhrin S. SumoPred-PLM: human SUMOylation and SUMO2/3 sites Prediction using Pre-trained Protein Language Model. NAR Genom Bioinform 2024; 6:lqae011. [PMID: 38327870 PMCID: PMC10849187 DOI: 10.1093/nargab/lqae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/17/2023] [Accepted: 01/17/2024] [Indexed: 02/09/2024] Open
Abstract
SUMOylation is an essential post-translational modification system with the ability to regulate nearly all aspects of cellular physiology. Three major paralogues SUMO1, SUMO2 and SUMO3 form a covalent bond between the small ubiquitin-like modifier with lysine residues at consensus sites in protein substrates. Biochemical studies continue to identify unique biological functions for protein targets conjugated to SUMO1 versus the highly homologous SUMO2 and SUMO3 paralogues. Yet, the field has failed to harness contemporary AI approaches including pre-trained protein language models to fully expand and/or recognize the SUMOylated proteome. Herein, we present a novel, deep learning-based approach called SumoPred-PLM for human SUMOylation prediction with sensitivity, specificity, Matthew's correlation coefficient, and accuracy of 74.64%, 73.36%, 0.48% and 74.00%, respectively, on the CPLM 4.0 independent test dataset. In addition, this novel platform uses contextualized embeddings obtained from a pre-trained protein language model, ProtT5-XL-UniRef50 to identify SUMO2/3-specific conjugation sites. The results demonstrate that SumoPred-PLM is a powerful and unique computational tool to predict SUMOylation sites in proteins and accelerate discovery.
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Affiliation(s)
- Andrew Vargas Palacios
- Department of Computer Science and Engineering Technology, University of Houston-Downtown, 1 Main St., Houston, TX 77002, USA
| | - Pujan Acharya
- Department of Computer Science and Engineering Technology, University of Houston-Downtown, 1 Main St., Houston, TX 77002, USA
| | - Anthony Stephen Peidl
- Department of Biology and Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, TX 77204, USA
| | - Moriah Rene Beck
- Department of Chemistry and Biochemistry, Wichita State University, 1845 Fairmount St., Wichita, KS 67260, USA
| | - Eduardo Blanco
- Department of Computer Science, University of Arizona, 1040 4th St., Tucson, AZ 85721, USA
| | - Avdesh Mishra
- Department of Electrical Engineering and Computer Science, Texas A&M University-Kingsville, Kingsville, TX 78363, USA
| | - Tasneem Bawa-Khalfe
- Department of Biology and Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, TX 77204, USA
| | - Subash Chandra Pakhrin
- Department of Computer Science and Engineering Technology, University of Houston-Downtown, 1 Main St., Houston, TX 77002, USA
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8
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Shi X, Dang X, Huang Z, Lu Y, Tong H, Liang F, Zhuang F, Li Y, Cai Z, Huo H, Jiang Z, Pan C, Wang X, Gu C, He B. SUMOylation of TEAD1 Modulates the Mechanism of Pathological Cardiac Hypertrophy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305677. [PMID: 38225750 PMCID: PMC10966521 DOI: 10.1002/advs.202305677] [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: 08/14/2023] [Revised: 12/14/2023] [Indexed: 01/17/2024]
Abstract
Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.
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Affiliation(s)
- Xin Shi
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Xuening Dang
- Department of Cardiovascular SurgeryShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Zhenyu Huang
- Department of Central LaboratoryShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Yanqiao Lu
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Huan Tong
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Feng Liang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Fei Zhuang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Yi Li
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Zhaohua Cai
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Huanhuan Huo
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Zhaolei Jiang
- Department of Cardiothoracic SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200030China
| | - Changqing Pan
- General Surgery DepartmentShanghai Chest HospitalSchool of Medicine Shanghai Jiao Tong UniversityShanghai200030China
| | - Xia Wang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Chang Gu
- Department of Cardiothoracic SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200030China
- Department of Thoracic SurgeryShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Ben He
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
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9
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Wang Y, Liu Z, Bian X, Zhao C, Zhang X, Liu X, Wang N. Function and regulation of ubiquitin-like SUMO system in heart. Front Cell Dev Biol 2023; 11:1294717. [PMID: 38033852 PMCID: PMC10687153 DOI: 10.3389/fcell.2023.1294717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023] Open
Abstract
The small ubiquitin-related modifier (SUMOylation) system is a conserved, reversible, post-translational protein modification pathway covalently attached to the lysine residues of proteins in eukaryotic cells, and SUMOylation is catalyzed by SUMO-specific activating enzyme (E1), binding enzyme (E2) and ligase (E3). Sentrin-specific proteases (SENPs) can cleave the isopeptide bond of a SUMO conjugate and catalyze the deSUMOylation reaction. SUMOylation can regulate the activity of proteins in many important cellular processes, including transcriptional regulation, cell cycle progression, signal transduction, DNA damage repair and protein stability. Biological experiments in vivo and in vitro have confirmed the key role of the SUMO conjugation/deconjugation system in energy metabolism, Ca2+ cycle homeostasis and protein quality control in cardiomyocytes. In this review, we summarized the research progress of the SUMO conjugation/deconjugation system and SUMOylation-mediated cardiac actions based on related studies published in recent years, and highlighted the further research areas to clarify the role of the SUMO system in the heart by using emerging technologies.
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Affiliation(s)
- Ying Wang
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin, China
| | - Zhihao Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiyun Bian
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin, China
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, China
| | - Chenxu Zhao
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Xin Zhang
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Xiaozhi Liu
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin, China
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, China
| | - Nan Wang
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
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10
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Zhao YQ, Jin HR, Kim D, Jung SH, Liu S, Wan J, Lo HY, Fu XQ, Wang Q, Hao C, Bellail AC. SUMO1 degrader induces ER stress and ROS accumulation through deSUMOylation of TCF4 and inhibition of its transcription of StarD7 in colon cancer. Mol Carcinog 2023; 62:1249-1262. [PMID: 37191369 PMCID: PMC10524896 DOI: 10.1002/mc.23560] [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: 11/16/2022] [Revised: 02/09/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023]
Abstract
Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screen has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader's anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).
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Affiliation(s)
- Yin Quan Zhao
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
- School of Life Sciences, Jilin University, Changchun, Jilin Province, 130012, China
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hong Ri Jin
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Daeho Kim
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sung Han Jung
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ho-Yin Lo
- Synovel Laboratory LLC, Danbury, CT 06811, USA
| | - Xue Qi Fu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, 130012, China
| | - Quan Wang
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Chunhai Hao
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Anita C. Bellail
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- HB Therapeutics Inc. Indianapolis, IN 46202, USA
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11
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Zhong Q, Xiao X, Qiu Y, Xu Z, Chen C, Chong B, Zhao X, Hai S, Li S, An Z, Dai L. Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications. MedComm (Beijing) 2023; 4:e261. [PMID: 37143582 PMCID: PMC10152985 DOI: 10.1002/mco2.261] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 05/06/2023] Open
Abstract
Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain and long-chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.
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Affiliation(s)
- Qian Zhong
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Xina Xiao
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Yijie Qiu
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Zhiqiang Xu
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Chunyu Chen
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Baochen Chong
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Xinjun Zhao
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Shan Hai
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Shuangqing Li
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Zhenmei An
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Lunzhi Dai
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
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12
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Lin X, Pang Q, Hu J, Sun J, Dai S, Yu Y, Xu J. SUMOylation mediates the disassembly of the Smad4 nuclear export complex via RanGAP1 in KELOIDS. J Cell Mol Med 2023; 27:1045-1055. [PMID: 36916534 PMCID: PMC10098277 DOI: 10.1111/jcmm.17216] [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: 09/23/2021] [Revised: 12/14/2021] [Accepted: 01/18/2022] [Indexed: 03/16/2023] Open
Abstract
Sentrin/small ubiquitin-like modifier (SUMO) has emerged as a powerful mediator regulating biological processes and participating in pathophysiological processes that cause human diseases, such as cancer, myocardial fibrosis and neurological disorders. Sumoylation has been shown to play a positive regulatory role in keloids. However, the sumoylation mechanism in keloids remains understudied. We proposed that sumoylation regulates keloids via a complex. RanGAP1 acted as a synergistic, functional partner of SUMOs in keloids. Nuclear accumulation of Smad4, a TGF-β/Smad pathway member, was associated with RanGAP1 after SUMO1 inhibition. RanGAP1*SUMO1 mediated the nuclear accumulation of Smad4 due to its impact on nuclear export and reduction in the dissociation of Smad4 and CRM1. We clarified a novel mechanism of positive regulation of sumoylation in keloids and demonstrated the function of sumoylation in Smad4 nuclear export. The NPC-associated RanGAP1*SUMO1 complex functions as a disassembly machine for the export receptor CRM1 and Smad4. Our research provides new perspectives for the mechanisms of keloids and nucleocytoplasmic transport.
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Affiliation(s)
- Xiaohu Lin
- Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qianqian Pang
- Ningbo Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Jie Hu
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiaqi Sun
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Siya Dai
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yijia Yu
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinghong Xu
- Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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13
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Wang W, Lu J, Yang WC, Spear ED, Michaelis S, Matunis MJ. Analysis of a degron-containing reporter protein GFP-CL1 reveals a role for SUMO1 in cytosolic protein quality control. J Biol Chem 2023; 299:102851. [PMID: 36587767 PMCID: PMC9898758 DOI: 10.1016/j.jbc.2022.102851] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022] Open
Abstract
Misfolded proteins are recognized and degraded through protein quality control (PQC) pathways, which are essential for maintaining proteostasis and normal cellular functions. Defects in PQC can result in disease, including cancer, cardiovascular disease, and neurodegeneration. The small ubiquitin-related modifiers (SUMOs) were previously implicated in the degradation of nuclear misfolded proteins, but their functions in cytoplasmic PQC are unclear. Here, in a systematic screen of SUMO protein mutations in the budding yeast Saccharomyces cerevisiae, we identified a mutant allele (Smt3-K38A/K40A) that sensitizes cells to proteotoxic stress induced by amino acid analogs. Smt3-K38A/K40A mutant strains also exhibited a defect in the turnover of a soluble PQC model substrate containing the CL1 degron (NES-GFP-Ura3-CL1) localized in the cytoplasm, but not the nucleus. Using human U2OS SUMO1- and SUMO2-KO cell lines, we observed a similar SUMO-dependent pathway for degradation of the mammalian degron-containing PQC reporter protein, GFP-CL1, also only in the cytoplasm but not the nucleus. Moreover, we found that turnover of GFP-CL1 in the cytoplasm was uniquely dependent on SUMO1 but not the SUMO2 paralogue. Additionally, we showed that turnover of GFP-CL1 in the cytoplasm is dependent on the AAA-ATPase, Cdc48/p97. Cellular fractionation studies and analysis of a SUMO1-GFP-CL1 fusion protein revealed that SUMO1 promotes cytoplasmic misfolded protein degradation by maintaining substrate solubility. Collectively, our findings reveal a conserved and previously unrecognized role for SUMO1 in regulating cytoplasmic PQC and provide valuable insights into the roles of sumoylation in PQC-associated diseases.
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Affiliation(s)
- Wei Wang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jian Lu
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Wei-Chih Yang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Eric D Spear
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
| | - Susan Michaelis
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
| | - Michael J Matunis
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
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14
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Liu Z, Liu X, Liu L, Wang Y, Zheng J, Li L, Li S, Zhang H, Ni J, Ma C, Gao X, Bian X, Fan G. SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity. J Pharm Anal 2023; 13:170-186. [PMID: 36908856 PMCID: PMC9999303 DOI: 10.1016/j.jpha.2022.11.010] [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: 07/14/2022] [Revised: 11/19/2022] [Accepted: 11/27/2022] [Indexed: 12/11/2022] Open
Abstract
Small ubiquitin-related modifier (SUMOylation) is a dynamic post-translational modification that maintains cardiac function and can protect against a hypertrophic response to cardiac pressure overload. However, the function of SUMOylation after myocardial infarction (MI) and the molecular details of heart cell responses to SUMO1 deficiency have not been determined. In this study, we demonstrated that SUMO1 protein was inconsistently abundant in different cell types and heart regions after MI. However, SUMO1 knockout significantly exacerbated systolic dysfunction and infarct size after myocardial injury. Single-nucleus RNA sequencing revealed the differential role of SUMO1 in regulating heart cells. Among cardiomyocytes, SUMO1 deletion increased the Nppa + Nppb + Ankrd1 + cardiomyocyte subcluster proportion after MI. In addition, the conversion of fibroblasts to myofibroblasts subclusters was inhibited in SUMO1 knockout mice. Importantly, SUMO1 loss promoted proliferation of endothelial cell subsets with the ability to reconstitute neovascularization and expressed angiogenesis-related genes. Computational analysis of ligand/receptor interactions suggested putative pathways that mediate cardiomyocytes to endothelial cell communication in the myocardium. Mice preinjected with cardiomyocyte-specific AAV-SUMO1, but not the endothelial cell-specific form, and exhibited ameliorated cardiac remodeling following MI. Collectively, our results identified the role of SUMO1 in cardiomyocytes, fibroblasts, and endothelial cells after MI. These findings provide new insights into SUMO1 involvement in the pathogenesis of MI and reveal novel therapeutic targets.
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Affiliation(s)
- Zhihao Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Xiaozhi Liu
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Li Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Ying Wang
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Jie Zheng
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Lan Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Sheng Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Han Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Jingyu Ni
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Xiumei Gao
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Xiyun Bian
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
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15
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García-Gutiérrez P, García-Domínguez M. SUMO control of nervous system development. Semin Cell Dev Biol 2022; 132:203-212. [PMID: 34848148 DOI: 10.1016/j.semcdb.2021.11.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022]
Abstract
In the last decades, the post-translational modification system by covalent attachment of the SUMO polypeptide to proteins has emerged as an essential mechanism controlling virtually all the physiological processes in the eukaryotic cell. This includes vertebrate development. In the nervous system, SUMO plays crucial roles in synapse establishment and it has also been linked to a variety of neurodegenerative diseases. However, to date, the involvement of the modification of specific targets in key aspects of nervous system development, like patterning and differentiation, has remained largely elusive. A number of recent works confirm the participation of target-specific SUMO modification in critical aspects of nervous system development. Here, we review pioneering and new findings demonstrating the essential role SUMO plays in neurogenesis and other facets of neurodevelopment, which will help to precisely understand the variety of mechanisms SUMO utilizes to control most fundamental processes in the cell.
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Affiliation(s)
- Pablo García-Gutiérrez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain
| | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain.
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16
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Zhang F, Zheng H, Xian Y, Song H, Wang S, Yun Y, Yi L, Zhang G. Profiling Substrate Specificity of the SUMO Protease Ulp1 by the YESS–PSSC System to Advance the Conserved Mechanism for Substrate Cleavage. Int J Mol Sci 2022; 23:ijms232012188. [PMID: 36293045 PMCID: PMC9603560 DOI: 10.3390/ijms232012188] [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] [Received: 09/12/2022] [Revised: 10/03/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022] Open
Abstract
SUMO modification is a vital post-translational regulation process in eukaryotes, in which the SUMO protease is responsible for the maturation of the SUMO precursor and the deconjugation of the SUMO protein from modified proteins by accurately cleaving behind the C-terminal Gly–Gly motif. To promote the understanding of the high specificity of the SUMO protease against the SUMO protein as well as to clarify whether the conserved Gly–Gly motif is strictly required for the processing of the SUMO precursor, we systematically profiled the specificity of the S. cerevisiae SUMO protease (Ulp1) on Smt3 at the P2–P1↓P1’ (Gly–Gly↓Ala) position using the YESS–PSSC system. Our results demonstrated that Ulp1 was able to cleave Gly–Gly↓ motif-mutated substrates, indicating that the diglycine motif is not strictly required for Ulp1 cleavage. A structural-modeling analysis indicated that it is the special tapered active pocket of Ulp1 conferred the selectivity of small residues at the P1–P2 position of Smt3, such as Gly, Ala, Ser and Cys, and only which can smoothly deliver the scissile bond into the active site for cleavage. Meanwhile, the P1’ position Ala of Smt3 was found to play a vital role in maintaining Ulp1’s precise cleavage after the Gly–Gly motif and replacing Ala with Gly in this position could expand Ulp1 inclusivity against the P1 and P2 position residues of Smt3. All in all, our studies advanced the traditional knowledge of the SUMO protein, which may provide potential directions for the drug discovery of abnormal SUMOylation-related diseases.
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Affiliation(s)
- Faying Zhang
- School of Life Sciences, Hubei University, Wuhan 430062, China
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Hui Zheng
- School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Yufan Xian
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Haoyue Song
- School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Shengchen Wang
- School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Yueli Yun
- School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Li Yi
- School of Life Sciences, Hubei University, Wuhan 430062, China
- Correspondence: (L.Y.); (G.Z.)
| | - Guimin Zhang
- School of Life Sciences, Hubei University, Wuhan 430062, China
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
- Correspondence: (L.Y.); (G.Z.)
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17
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Vertegaal ACO. Signalling mechanisms and cellular functions of SUMO. Nat Rev Mol Cell Biol 2022; 23:715-731. [PMID: 35750927 DOI: 10.1038/s41580-022-00500-y] [Citation(s) in RCA: 171] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2022] [Indexed: 12/22/2022]
Abstract
Sumoylation is an essential post-translational modification that is catalysed by a small number of modifying enzymes but regulates thousands of target proteins in a dynamic manner. Small ubiquitin-like modifiers (SUMOs) can be attached to target proteins as one or more monomers or in the form of polymers of different types. Non-covalent readers recognize SUMO-modified proteins via SUMO interaction motifs. SUMO simultaneously modifies groups of functionally related proteins to regulate predominantly nuclear processes, including gene expression, the DNA damage response, RNA processing, cell cycle progression and proteostasis. Recent progress has increased our understanding of the cellular and pathophysiological roles of SUMO modifications, extending their functions to the regulation of immunity, pluripotency and nuclear body assembly in response to oxidative stress, which partly occurs through the recently characterized mechanism of liquid-liquid phase separation. Such progress in understanding the roles and regulation of sumoylation opens new avenues for the targeting of SUMO to treat disease, and indeed the first drug blocking sumoylation is currently under investigation in clinical trials as a possible anticancer agent.
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Affiliation(s)
- Alfred C O Vertegaal
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
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18
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Insights in Post-Translational Modifications: Ubiquitin and SUMO. Int J Mol Sci 2022; 23:ijms23063281. [PMID: 35328702 PMCID: PMC8952880 DOI: 10.3390/ijms23063281] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/23/2022] Open
Abstract
Both ubiquitination and SUMOylation are dynamic post-translational modifications that regulate thousands of target proteins to control virtually every cellular process. Unfortunately, the detailed mechanisms of how all these cellular processes are regulated by both modifications remain unclear. Target proteins can be modified by one or several moieties, giving rise to polymers of different morphology. The conjugation cascades of both modifications comprise a few activating and conjugating enzymes but close to thousands of ligating enzymes (E3s) in the case of ubiquitination. As a result, these E3s give substrate specificity and can form polymers on a target protein. Polymers can be quickly modified forming branches or cleaving chains leading the target protein to its cellular fate. The recent development of mass spectrometry(MS) -based approaches has increased the understanding of ubiquitination and SUMOylation by finding essential modified targets in particular signaling pathways. Here, we perform a concise overview comprising from the basic mechanisms of both ubiquitination and SUMOylation to recent MS-based approaches aimed to find specific targets for particular E3 enzymes.
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19
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Sumoylation in Physiology, Pathology and Therapy. Cells 2022; 11:cells11050814. [PMID: 35269436 PMCID: PMC8909597 DOI: 10.3390/cells11050814] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 02/04/2023] Open
Abstract
Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations.
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20
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SUMOylation regulates the number and size of promyelocytic leukemia-nuclear bodies (PML-NBs) and arsenic perturbs SUMO dynamics on PML by insolubilizing PML in THP-1 cells. Arch Toxicol 2022; 96:545-558. [PMID: 35001170 DOI: 10.1007/s00204-021-03195-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/10/2021] [Indexed: 11/02/2022]
Abstract
The functional roles of protein modification by small ubiquitin-like modifier (SUMO) proteins are not well understood compared to ubiquitination. Promyelocytic leukemia (PML) proteins are good substrates for SUMOylation, and PML-nuclear bodies (PML-NBs) may function as a platform for the PML SUMOylation. PML proteins are rapidly modified both with SUMO2/3 and SUMO1 after exposure to arsenite (As3+) and SUMOylated PML are further ubiquitinated and degraded by proteasomes. However, effects of As3+ on SUMO dynamics on PML-NBs are not well investigated. In the present study, we report that (1) the number and size of PML-NBs were regulated by SUMO E1-activating enzyme, (2) SUMO2/3 co-localized with PML irrespective of As3+ exposure and was restricted to PML-nuclear bodies (PML-NBs) via covalent binding in response to As3+, and (3) As3+-induced biochemical changes in PML were not modulated by ubiquitin-proteasome system (UPS) in THP-1 cells. Undifferentiated and differentiated THP-1 cells responded to As3+ similarly and PML proteins were changed from the detergent soluble to the insoluble form and further SUMOylated with SUMO2/3 and SUMO1. ML792, a SUMO E1 inhibitor, decreased the number of PML-NBs and reciprocally increased the size irrespective of exposure to As3+, which itself slightly decrease both the number and size of PML-NBs. TAK243, a ubiquitin E1 inhibitor, did not change the PML-NBs, while SUMOylated proteins accumulated in the TAK243-exposed cells. Proteasome inhibitors did not change the As3+-induced SUMOylation levels of PML. Co-localization and further restriction of SUMO2/3 to PML-NBs were confirmed by PML-transfected CHO-K1 cells. Collectively, SUMOylation regulates PML-NBs and As3+ restricts SUMO dynamics on PML by changing its solubility.
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21
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In vitro and in cellulae methods for determining the target protein SUMOylation. Methods Enzymol 2022; 675:397-424. [DOI: 10.1016/bs.mie.2022.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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22
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Hotz PW, Müller S, Mendler L. SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease. Front Mol Biosci 2021; 8:786136. [PMID: 34869605 PMCID: PMC8641784 DOI: 10.3389/fmolb.2021.786136] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022] Open
Abstract
SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.
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Affiliation(s)
- Paul W Hotz
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Stefan Müller
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Luca Mendler
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
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23
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Bellail AC, Jin HR, Lo HY, Jung SH, Hamdouchi C, Kim D, Higgins RK, Blanck M, le Sage C, Cross BCS, Li J, Mosley AL, Wijeratne AB, Jiang W, Ghosh M, Zhao YQ, Hauck PM, Shekhar A, Hao C. Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors. Sci Transl Med 2021; 13:eabh1486. [PMID: 34644148 DOI: 10.1126/scitranslmed.abh1486] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Anita C Bellail
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.,HB Therapeutics Inc., Indianapolis, IN 46202, USA
| | - Hong Ri Jin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ho-Yin Lo
- Synovel Laboratory LLC, Danbury, CT 06811, USA
| | - Sung Han Jung
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chafiq Hamdouchi
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Daeho Kim
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ryan K Higgins
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | | | | | - Jing Li
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Amber L Mosley
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Aruna B Wijeratne
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Wen Jiang
- Department of Biological Sciences, Markey Center for Structural Biology, Purdue University, West Lafayette, IN 47907, USA
| | - Manali Ghosh
- Department of Biological Sciences, Markey Center for Structural Biology, Purdue University, West Lafayette, IN 47907, USA
| | - Yin Quan Zhao
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Paula M Hauck
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Anantha Shekhar
- Department of Psychiatry and Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chunhai Hao
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.,Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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24
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Yoshioka H, Li A, Suzuki A, Ramakrishnan SS, Zhao Z, Iwata J. Identification of microRNAs and gene regulatory networks in cleft lip common in humans and mice. Hum Mol Genet 2021; 30:1881-1893. [PMID: 34104955 PMCID: PMC8444451 DOI: 10.1093/hmg/ddab151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/17/2021] [Accepted: 05/31/2021] [Indexed: 12/11/2022] Open
Abstract
The etiology of cleft lip with/without cleft palate (CL/P), one of the most frequent craniofacial birth defects worldwide, is complicated by contributions of both genetic and environmental factors. Understanding the etiology of these conditions is essential for developing preventive strategies. This study thus aims to identify regulatory networks of microRNAs (miRNAs), transcriptional factors (TFs) and non-TF genes associated with cleft lip (CL) that are conserved in humans and mice. Notably, we found that miR-27b, miR-133b, miR-205, miR-376b and miR-376c were involved in the regulation of CL-associated gene expression in both humans and mice. Among the candidate miRNAs, the overexpression of miR-27b, miR-133b and miR-205, but not miR-376b and miR-376c, significantly inhibited cell proliferation through suppression of CL-associated genes (miR-27b suppressed PAX9 and RARA; miR-133b suppressed FGFR1, PAX7, and SUMO1; and miR-205 suppressed PAX9 and RARA) in cultured human and mouse lip mesenchymal cells. Taken together, our results suggest that elevated expression of miR-27b, miR-133b and miR-205 may play a crucial role in CL through the suppression of genes associated with CL.
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Affiliation(s)
- Hiroki Yoshioka
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Aimin Li
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Akiko Suzuki
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Sai Shankar Ramakrishnan
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Junichi Iwata
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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25
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Li W, Chopp M, Zacharek A, Yang W, Chen Z, Landschoot-Ward J, Venkat P, Chen J. SUMO1 Deficiency Exacerbates Neurological and Cardiac Dysfunction after Intracerebral Hemorrhage in Aged Mice. Transl Stroke Res 2021; 12:631-642. [PMID: 32761461 DOI: 10.1007/s12975-020-00837-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/28/2020] [Indexed: 01/14/2023]
Abstract
Small ubiquitin-like modifier 1 (SUMO1) reduces cardiac hypertrophy and induces neuroprotective effects. Previous studies have found that intracerebral hemorrhage (ICH) provokes cardiac deficit in the absence of primary cardiac diseases in mice. In this study, we tested the hypothesis that SUMO1 deficiency leads to worse brain and heart dysfunction after ICH and SUMO1 plays a key role in regulating brain-heart interaction after ICH in aged mice. Aged (18-20 months) female SUMO1 null (SUMO1-/-) mice and wild-type (WT) C57BL/6 J mice were randomly divided into four groups (n = 8/group): (1) WT-sham group, (2) SUMO1-/--sham group, (3) WT-ICH group, and (4) SUMO1-/--ICH group. Cardiac function was measured by echocardiography. Neurological and cognitive functional tests were performed. Mice were sacrificed at 10 days after ICH for histological and immunohistochemically staining. Compared with WT-sham mice, WT-ICH mice exhibited (1) significantly (P < 0.05) decreased SUMO1 expression in heart tissue, (2) evident neurological and cognitive dysfunction as well as brain white matter deficits, (3) significantly increased cardiac dysfunction, and (4) inflammatory factor expression in the heart and brain. Compared with WT-ICH mice, SUMO1-/--ICH mice exhibited significantly increased: (1) brain hemorrhage volume, worse neurological and cognitive deficits, and increased white matter deficits; (2) cardiac dysfunction and cardiac fibrosis; (3) inflammatory response both in heart and brain tissue. Aged SUMO1-deficient female mice subjected to ICH not only exhibit increased neurological and cognitive functional deficit but also significantly increased cardiac dysfunction and inflammatory cell infiltration into the heart and brain. These data suggest that SUMO1 plays an important role in brain-heart interaction.
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Affiliation(s)
- Wei Li
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA
- Department of Physics, Oakland University, Rochester, MI-48309, USA
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA
| | - Wei Yang
- Department of Anesthesiology, Duke University Medical Center, Durham, NC-27710, USA
| | - Zhili Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA
| | | | - Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA.
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26
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Chen LC, Hsieh YL, Tan GYT, Kuo TY, Chou YC, Hsu PH, Hwang-Verslues WW. Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function. Sci Rep 2021; 11:14431. [PMID: 34257372 PMCID: PMC8277905 DOI: 10.1038/s41598-021-93933-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 07/05/2021] [Indexed: 11/09/2022] Open
Abstract
Posttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2 interaction with β-TrCP leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation, inhibited PER2 degradation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter PER2 protein oscillation and reduce PER2-mediated transcriptional suppression. Together, our data revealed that SUMO1 versus SUMO2 conjugation acts as a determinant of PER2 stability and function and thereby affects the circadian regulatory system and the expression of clock-controlled genes.
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Affiliation(s)
- Ling-Chih Chen
- Genomics Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Taipei, 115, Taiwan, ROC
| | - Yung-Lin Hsieh
- Genomics Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Taipei, 115, Taiwan, ROC
| | - Grace Y T Tan
- Genomics Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Taipei, 115, Taiwan, ROC
| | - Tai-Yun Kuo
- Genomics Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Taipei, 115, Taiwan, ROC
| | - Yu-Chi Chou
- Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, 115, Taiwan, ROC
| | - Pang-Hung Hsu
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung City, 202, Taiwan, ROC
| | - Wendy W Hwang-Verslues
- Genomics Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Taipei, 115, Taiwan, ROC.
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27
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Bouchard D, Wang W, Yang WC, He S, Garcia A, Matunis MJ. SUMO paralogue-specific functions revealed through systematic analysis of human knockout cell lines and gene expression data. Mol Biol Cell 2021; 32:1849-1866. [PMID: 34232706 PMCID: PMC8684707 DOI: 10.1091/mbc.e21-01-0031] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The small ubiquitin-related modifiers (SUMOs) regulate nearly every aspect of cellular function, from gene expression in the nucleus to ion transport at the plasma membrane. In humans, the SUMO pathway has five SUMO paralogues with sequence homologies that range from 45% to 97%. SUMO1 and SUMO2 are the most distantly related paralogues and also the best studied. To what extent SUMO1, SUMO2, and the other paralogues impart unique and nonredundant effects on cellular functions, however, has not been systematically examined and is therefore not fully understood. For instance, knockout studies in mice have revealed conflicting requirements for the paralogues during development and studies in cell culture have relied largely on transient paralogue overexpression or knockdown. To address the existing gap in understanding, we first analyzed SUMO paralogue gene expression levels in normal human tissues and found unique patterns of SUMO1–3 expression across 30 tissue types, suggesting paralogue-specific functions in adult human tissues. To systematically identify and characterize unique and nonredundant functions of the SUMO paralogues in human cells, we next used CRISPR-Cas9 to knock out SUMO1 and SUMO2 expression in osteosarcoma (U2OS) cells. Analysis of these knockout cell lines revealed essential functions for SUMO1 and SUMO2 in regulating cellular morphology, promyelocytic leukemia (PML) nuclear body structure, responses to proteotoxic and genotoxic stress, and control of gene expression. Collectively, our findings reveal nonredundant regulatory roles for SUMO1 and SUMO2 in controlling essential cellular processes and provide a basis for more precise SUMO-targeting therapies.
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Affiliation(s)
- Danielle Bouchard
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Wei Wang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Wei-Chih Yang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Shuying He
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Anthony Garcia
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Michael J Matunis
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
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28
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Nie Q, Chen H, Zou M, Wang L, Hou M, Xiang JW, Luo Z, Gong XD, Fu JL, Wang Y, Zheng SY, Xiao Y, Gan YW, Gao Q, Bai YY, Wang JM, Zhang L, Tang XC, Hu X, Gong L, Liu Y, Li DWC. The E3 Ligase PIAS1 Regulates p53 Sumoylation to Control Stress-Induced Apoptosis of Lens Epithelial Cells Through the Proapoptotic Regulator Bax. Front Cell Dev Biol 2021; 9:660494. [PMID: 34195189 PMCID: PMC8237824 DOI: 10.3389/fcell.2021.660494] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/20/2021] [Indexed: 01/31/2023] Open
Abstract
Protein sumoylation is one of the most important post-translational modifications regulating many biological processes (Flotho A & Melchior F. 2013. Ann Rev. Biochem. 82:357–85). Our previous studies have shown that sumoylation plays a fundamental role in regulating lens differentiation (Yan et al., 2010. PNAS, 107(49):21034-9.; Gong et al., 2014. PNAS. 111(15):5574–9). Whether sumoylation is implicated in lens pathogenesis remains elusive. Here, we present evidence to show that the protein inhibitor of activated STAT-1 (PIAS1), a E3 ligase for sumoylation, is implicated in regulating stress-induced lens pathogenesis. During oxidative stress-induced cataractogenesis, expression of PIAS1 is significantly altered at both mRNA and protein levels. Upregulation and overexpression of exogenous PIAS1 significantly enhances stress-induced apoptosis. In contrast, silence of PIAS1 with CRISPR/Cas9 technology attenuates stress-induced apoptosis. Mechanistically, different from other cells, PIAS1 has little effect to activate JNK but upregulates Bax, a major proapoptotic regulator. Moreover, Bax upregulation is derived from the enhanced transcription activity of the upstream transcription factor, p53. As revealed previously in other cells by different laboratories, our data also demonstrate that PIAS1 promotes SUMO1 conjugation of p53 at K386 residue in lens epithelial cells and thus enhances p53 transcription activity to promote Bax upregulation. Silence of Bax expression largely abrogates PIAS1-mediated enhancement of stress-induced apoptosis. Thus, our results demonstrated that PIAS1 promotes oxidative stress-induced apoptosis through positive control of p53, which specifically upregulates expression of the downstream proapoptotic regulator Bax. As a result, PIAS1-promoted apoptosis induced by oxidative stress is implicated in lens pathogenesis.
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Affiliation(s)
- Qian Nie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Huimin Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ming Zou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ling Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Min Hou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia-Wen Xiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhongwen Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Dong Gong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia-Ling Fu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yan Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shu-Yu Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yuan Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yu-Wen Gan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qian Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yue-Yue Bai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jing-Miao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lan Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiang-Cheng Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuebin Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lili Gong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yizhi Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - David Wan-Cheng Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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29
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Yang Y, Zhang Y, Qiao P, Yang B, Jia H, Zhang Y, Zhang J, Su J. SUMO2, a small ubiquitin-like modifier, is essential for development of murine preimplantation embryos. Theriogenology 2021; 166:29-37. [PMID: 33677127 DOI: 10.1016/j.theriogenology.2021.01.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 11/17/2022]
Abstract
Small ubiquitin-like modifier 2 (SUMO2) is a small protein that modulates the stability and activity of other proteins. Although a variety of activities have been attributed to SUMO2, its function in preimplantation embryos is still obscure. We first explored the expression of SUMO2 protein in early embryos, and showed that compared with the 2-cell stage, the expression was increased at first, peaked at the 8-cell stage, and then dramatically decreased. To study the function of SUMO2, we used siRNA microinjection to knock down SUMO2.The silencing of SUMO2 significantly reduced the rate of in vitro blastocyst development from 75.56% to 40.60%. Notably, knockdown of SUMO2 (KD) altered the expression of CDX2, OCT4, and NANOG. The number of cells expressing CDX2 decreased, while OCT4 and NANOG were ectopically expressed in siSUMO2 embryos. The global H3K27me3 levels in SUMO2-KD embryos also were lower than in untreated embryos. Taken together, SUMO2 appears to play a significant role in mouse preimplantation embryos probably through key epigenetic modifications and regulation of pluripotency genes.
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Affiliation(s)
- Ying Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Yingbing Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Peipei Qiao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Bin Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Huiqun Jia
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Yong Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China
| | - Jun Zhang
- Academy of Animal Science and Veterinary Medicine, Qinghai University, Xining, Qinghai Province, 810016, PR China.
| | - Jianmin Su
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China.
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30
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The role of SUMOylation during development. Biochem Soc Trans 2021; 48:463-478. [PMID: 32311032 PMCID: PMC7200636 DOI: 10.1042/bst20190390] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/17/2022]
Abstract
During the development of multicellular organisms, transcriptional regulation plays an important role in the control of cell growth, differentiation and morphogenesis. SUMOylation is a reversible post-translational process involved in transcriptional regulation through the modification of transcription factors and through chromatin remodelling (either modifying chromatin remodelers or acting as a ‘molecular glue’ by promoting recruitment of chromatin regulators). SUMO modification results in changes in the activity, stability, interactions or localization of its substrates, which affects cellular processes such as cell cycle progression, DNA maintenance and repair or nucleocytoplasmic transport. This review focuses on the role of SUMO machinery and the modification of target proteins during embryonic development and organogenesis of animals, from invertebrates to mammals.
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31
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Abstract
Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.
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Affiliation(s)
- Hui-Ming Chang
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Edward T H Yeh
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
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32
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Jansen NS, Vertegaal ACO. A Chain of Events: Regulating Target Proteins by SUMO Polymers. Trends Biochem Sci 2020; 46:113-123. [PMID: 33008689 DOI: 10.1016/j.tibs.2020.09.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/21/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023]
Abstract
Small ubiquitin-like modifiers (SUMOs) regulate virtually all nuclear processes. The fate of the target protein is determined by the architecture of the attached SUMO protein, which can be of polymeric nature. Here, we highlight the multifunctional aspects of dynamic signal transduction by SUMO polymers. The SUMO-targeted ubiquitin ligases (STUbLs) RING-finger protein 4 (RNF4) and RNF111 recognize SUMO polymers in a chain-architecture-dependent manner, leading to the formation of hybrid chains, which could enable proteasomal destruction of proteins. Recent publications have highlighted essential roles for SUMO chain disassembly by the mammalian SUMO proteases SENP6 and SENP7 and the yeast SUMO protease Ulp2. SENP6 is particularly important for centromere assembly. These recent findings demonstrate the diversity of SUMO polymer signal transduction for proteolytic and nonproteolytic purposes.
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Affiliation(s)
- Nicolette S Jansen
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands
| | - Alfred C O Vertegaal
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
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33
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Yu S, Galeffi F, Rodriguiz RM, Wang Z, Shen Y, Lyu J, Li R, Bernstock JD, Johnson KR, Liu S, Sheng H, Turner DA, Wetsel WC, Paschen W, Yang W. Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice. FASEB J 2020; 34:14750-14767. [PMID: 32910521 DOI: 10.1096/fj.202000850rr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/15/2022]
Abstract
Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1-3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal-based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long-term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.
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Affiliation(s)
- Shu Yu
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.,Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Francesca Galeffi
- Research and Surgery Services, Durham VAMC, Durham, NC, USA.,Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.,Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.,Department of Biomedical Engineering, Duke University Medical Center, Durham, NC, USA
| | - Ramona M Rodriguiz
- Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA
| | - Zhuoran Wang
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Yuntian Shen
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.,Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jingjun Lyu
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ran Li
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Joshua D Bernstock
- Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - Kory R Johnson
- Bioinformatics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - Shuai Liu
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Huaxin Sheng
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Dennis A Turner
- Research and Surgery Services, Durham VAMC, Durham, NC, USA.,Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.,Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.,Department of Biomedical Engineering, Duke University Medical Center, Durham, NC, USA
| | - William C Wetsel
- Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.,Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.,Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
| | - Wulf Paschen
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Wei Yang
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
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34
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Gillon A, Steel C, Cornwall J, Sheard P. Increased nuclear permeability is a driver for age-related motoneuron loss. GeroScience 2020; 42:833-847. [PMID: 32002784 PMCID: PMC7286994 DOI: 10.1007/s11357-020-00155-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 01/09/2020] [Indexed: 12/11/2022] Open
Abstract
Sarcopenia is the loss of skeletal muscle mass with age, the precise cause of which remains unclear. Several studies have shown that sarcopenia is at least partly driven by denervation which, in turn, is related to loss of motor nerve cells. Recent data suggests degradation of the nucleocytoplasmic barrier and nuclear envelope transport process are contributors to nerve loss in a number of neurodegenerative diseases. Having recently shown that important components of the nuclear barrier are lost with advancing age, we now ask whether these emergent defects accompany increased nuclear permeability, chromatin disorganization and lower motoneuron loss in normal ageing, and if so, whether exercise attenuates these changes. Immunohistochemistry was used on young adult, old and exercised mouse tissues to examine nucleocytoplasmic transport regulatory proteins and chromatin organization. We used a nuclear permeability assay to investigate the patency of the nuclear barrier on extracts of the spinal cord from each group. We found increased permeability in nuclei isolated from spinal cords of old animals that correlated with both mislocalization of essential nuclear transport proteins and chromatin disorganization, and also found that in each case, exercise attenuated the age-associated changes. Findings suggest that the loss of nuclear barrier integrity in combination with previously described defects in nucleocytoplasmic transport may drive increased nuclear permeability and contribute to age-related motoneuron death. These events may be significant indirect drivers of skeletal muscle loss.
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Affiliation(s)
- Ashley Gillon
- Department of Physiology, School of Biomedical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand
| | - Charlotte Steel
- Department of Physiology, School of Biomedical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand
| | - Jon Cornwall
- Centre for Early Learning in Medicine, Otago Medical School, University of Otago, Dunedin, New Zealand
| | - Philip Sheard
- Department of Physiology, School of Biomedical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand
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35
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Celen AB, Sahin U. Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts. FEBS J 2020; 287:3110-3140. [DOI: 10.1111/febs.15319] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/04/2020] [Accepted: 03/30/2020] [Indexed: 12/26/2022]
Affiliation(s)
- Arda B. Celen
- Department of Molecular Biology and Genetics Center for Life Sciences and Technologies Bogazici University Istanbul Turkey
| | - Umut Sahin
- Department of Molecular Biology and Genetics Center for Life Sciences and Technologies Bogazici University Istanbul Turkey
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36
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Rabellino A, Khanna KK. The implication of the SUMOylation pathway in breast cancer pathogenesis and treatment. Crit Rev Biochem Mol Biol 2020; 55:54-70. [PMID: 32183544 DOI: 10.1080/10409238.2020.1738332] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed malignancy in woman worldwide, and is the second most common cause of death in developed countries. The transformation of a normal cell into a malignant derivate requires the acquisition of diverse genomic and proteomic changes, including enzymatic post-translational modifications (PTMs) on key proteins encompassing critical cell signaling events. PTMs occur on proteins after translation, and regulate several aspects of proteins activity, including their localization, activation and turnover. Deregulation of PTMs can potentially lead to tumorigenesis, and several de-regulated PTM pathways contribute to abnormal cell proliferation during breast tumorigenesis. SUMOylation is a PTM that plays a pivotal role in numerous aspects of cell physiology, including cell cycle regulation, protein trafficking and turnover, and DNA damage repair. Consistently with this, the deregulation of the SUMO pathway is observed in different human pathologies, including breast cancer. In this review we will describe the role of SUMOylation in breast tumorigenesis and its implication for breast cancer therapy.
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Affiliation(s)
- Andrea Rabellino
- QIMR Berghofer Medical Research Institute, Brisbane City, Australia
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research Institute, Brisbane City, Australia
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37
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Nayak A, Amrute-Nayak M. SUMO system - a key regulator in sarcomere organization. FEBS J 2020; 287:2176-2190. [PMID: 32096922 DOI: 10.1111/febs.15263] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/07/2020] [Accepted: 02/24/2020] [Indexed: 01/14/2023]
Abstract
Skeletal muscles constitute roughly 40% of human body mass. Muscles are specialized tissues that generate force to drive movements through ATP-driven cyclic interactions between the protein filaments, namely actin and myosin filaments. The filaments are organized in an intricate structure called the 'sarcomere', which is a fundamental contractile unit of striated skeletal and cardiac muscle, hosting a fine assembly of macromolecular protein complexes. The micrometer-sized sarcomere units are arranged in a reiterated array within myofibrils of muscle cells. The precise spatial organization of sarcomere is tightly controlled by several molecular mechanisms, indispensable for its force-generating function. Disorganized sarcomeres, either due to erroneous molecular signaling or due to mutations in the sarcomeric proteins, lead to human diseases such as cardiomyopathies and muscle atrophic conditions prevalent in cachexia. Protein post-translational modifications (PTMs) of the sarcomeric proteins serve a critical role in sarcomere formation (sarcomerogenesis), as well as in the steady-state maintenance of sarcomeres. PTMs such as phosphorylation, acetylation, ubiquitination, and SUMOylation provide cells with a swift and reversible means to adapt to an altered molecular and therefore cellular environment. Over the past years, SUMOylation has emerged as a crucial modification with implications for different aspects of cell function, including organizing higher-order protein assemblies. In this review, we highlight the fundamentals of the small ubiquitin-like modifiers (SUMO) pathway and its link specifically to the mechanisms of sarcomere assembly. Furthermore, we discuss recent studies connecting the SUMO pathway-modulated protein homeostasis with sarcomere organization and muscle-related pathologies.
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Affiliation(s)
- Arnab Nayak
- Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany
| | - Mamta Amrute-Nayak
- Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany
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38
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Cabrita MA, Renart LI, Lau R, Pratt MAC. Intrinsically Disordered SRC-3/AIB1 Protein Undergoes Homeostatic Nuclear Extrusion by Nuclear Budding While Ectopic Expression Induces Nucleophagy. Cells 2019; 8:cells8101278. [PMID: 31635050 PMCID: PMC6830083 DOI: 10.3390/cells8101278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/12/2019] [Accepted: 10/17/2019] [Indexed: 11/16/2022] Open
Abstract
SRC-3/AIB1 (Amplified in Breast Cancer-1) is a nuclear receptor coactivator for the estrogen receptor in breast cancer cells. It is also an intrinsically disordered protein when not engaged with transcriptional binding partners and degraded upon transcriptional coactivation. Given the amplified expression of SRC-3 in breast cancers, the objective of this study was to determine how increasing SRC-3 protein levels are regulated in MCF-7 breast cancer cells. We found that endogenous SRC-3 was expelled from the nucleus in vesicle-like spheres under normal growth conditions suggesting that this form of nuclear exclusion of SRC-3 is a homeostatic mechanism for regulating nuclear SRC-3 protein. Only SRC-3 not associated with CREB-binding protein (CBP) was extruded from the nucleus. We found that overexpression in MCF-7 cells results in aneuploid senescence and cell death with frequent formation of nuclear aggregates which were consistently juxtaposed to perinuclear microtubules. Transfected SRC-3 was SUMOylated and caused redistribution of nuclear promyelocytic leukemia (PML) bodies and perturbation of the nuclear membrane lamin B1, hallmarks of nucleophagy. Increased SRC-3 protein-induced autophagy and resulted in SUMO-1 localization to the nuclear membrane and formation of protrusions variously containing SRC-3 and chromatin. Aspects of SRC-3 overexpression and toxicity were recapitulated following treatment with clinically relevant agents that stabilize SRC-3 in breast cancer cells. We conclude that amplified SRC-3 levels have major impacts on nuclear protein quality control pathways and may mark cancer cells for sensitivity to protein stabilizing therapeutics.
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Affiliation(s)
- Miguel A Cabrita
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - L Isabel Renart
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Rosanna Lau
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - M A Christine Pratt
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
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39
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Li J, Johnson JA, Su H. Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection. Curr Drug Targets 2019; 19:989-1002. [PMID: 26648080 DOI: 10.2174/1389450117666151209114608] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 11/01/2015] [Indexed: 01/10/2023]
Abstract
Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases.
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Affiliation(s)
- Jie Li
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - John A Johnson
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Huabo Su
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
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40
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Wu Q, Aroankins TS, Cheng L, Fenton RA. SUMOylation Landscape of Renal Cortical Collecting Duct Cells. J Proteome Res 2019; 18:3640-3648. [PMID: 31502464 DOI: 10.1021/acs.jproteome.9b00306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Protein post-translational modification by the small ubiquitin-like modifier (SUMO) is a mechanism that allows a diverse response of cells to stress. Five SUMO family members, SUMO1-5, are expressed in mammals. We hypothesized that because kidney epithelial cells are often subject to stresses arising from various physiological conditions, multiple proteins in the kidney will be SUMOylated. Here, we profiled SUMO1- and SUMO2-modified proteins in a polarized epithelial cell model of the renal cortical collecting duct (mpkCCD14 cells). Modified forms of SUMO1 or SUMO2, with a histidine tag and a Thr to Lys mutation preceding the carboxyl-terminal di-gly motif, were expressed in mpkCCD14 cells, allowing SUMO-conjugated proteins to be purified and identified. Protein mass spectrometry identified 1428 SUMO1 and 1957 SUMO2 sites, corresponding to 741 SUMO1 and 971 SUMO2 proteins. Gene ontology indicated that the function of the majority of SUMOylated proteins in mpkCCD14 cells was related to gene transcription. After treatment of the mpkCCD14 cells for 24 h with aldosterone, the levels of SUMOylation at a specific site on the proton and oligopeptide/antibiotic cotransporter protein Pept2 were greatly increased. In conclusion, the SUMOylation landscape of mpkCCD14 cells suggests that protein modification by SUMOylation is a mechanism within renal epithelial cells to modulate gene transcription under various physiological conditions.
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Affiliation(s)
- Qi Wu
- InterPrET Center, Department of Biomedicine , Aarhus University , Aarhus DK-8000 , Denmark
| | - Takwa S Aroankins
- InterPrET Center, Department of Biomedicine , Aarhus University , Aarhus DK-8000 , Denmark
| | - Lei Cheng
- InterPrET Center, Department of Biomedicine , Aarhus University , Aarhus DK-8000 , Denmark
| | - Robert A Fenton
- InterPrET Center, Department of Biomedicine , Aarhus University , Aarhus DK-8000 , Denmark
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41
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Bertke MM, Dubiak KM, Cronin L, Zeng E, Huber PW. A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos. BMC Genomics 2019; 20:386. [PMID: 31101013 PMCID: PMC6525467 DOI: 10.1186/s12864-019-5773-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 05/03/2019] [Indexed: 02/08/2023] Open
Abstract
Background Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cell Xenopus embryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development. Results We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and heart development. We have measured differences in gene expression between control and embryos injected with Gam1 mRNA at three developmental stages: early gastrula (immediately following the initiation of zygotic transcription), late gastrula (completion of the formation of the three primary germ layers), and early neurula (appearance of the neural plate). Although changes in gene expression are widespread and can be linked to many biological processes, three pathways, non-canonical Wnt/PCP, snail/twist, and Ets-1, are especially sensitive to the loss of SUMOylation activity and can largely account for the predominant phenotypes of Gam1 embryos. SUMOylation appears to generate different pools of a given transcription factor having different specificities with this post-translational modification involved in the regulation of more complex, as opposed to housekeeping, processes. Conclusions We have identified changes in gene expression that underlie the neural tube and heart phenotypes resulting from depressed SUMOylation activity. Notably, these developmental defects correspond to the two most frequently occurring congenital birth defects in humans, strongly suggesting that perturbation of SUMOylation, either globally or of a specific protein, may frequently be the origin of these pathologies. Electronic supplementary material The online version of this article (10.1186/s12864-019-5773-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Michelle M Bertke
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, 46556, USA.,Present Address: College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD, 20742, USA
| | - Kyle M Dubiak
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, 46556, USA
| | - Laura Cronin
- Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, Indiana, 46556, USA
| | - Erliang Zeng
- Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, Indiana, 46556, USA.,Present Address: Division of Biostatistics and Computational Biology, Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, 52242, USA.,Present Address: Department of Preventive & Community Dentistry, College of Dentistry, University of Iowa, Iowa City, IA, 52242, USA.,Present Address: Department of Biostatistics, University of Iowa, Iowa City, IA, 52242, USA.,Present Address: Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52242, USA
| | - Paul W Huber
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, 46556, USA. .,Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA. .,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana, 46556, USA.
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42
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Fox BM, Janssen A, Estevez-Ordonez D, Gessler F, Vicario N, Chagoya G, Elsayed G, Sotoudeh H, Stetler W, Friedman GK, Bernstock JD. SUMOylation in Glioblastoma: A Novel Therapeutic Target. Int J Mol Sci 2019; 20:ijms20081853. [PMID: 30991648 PMCID: PMC6514907 DOI: 10.3390/ijms20081853] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/11/2019] [Accepted: 04/11/2019] [Indexed: 12/22/2022] Open
Abstract
Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.
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Affiliation(s)
- Brandon M Fox
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
- Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA.
| | - Andrew Janssen
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
| | - Dagoberto Estevez-Ordonez
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
| | - Florian Gessler
- Department of Neurosurgery, University Hospital Frankfurt, Goethe-University, Schleusenweg 2-16, 60528 Frankfurt, Germany.
| | - Nunzio Vicario
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Via S. Sofia n. 97, Torre Biologica, 95123 Catania, Italy.
| | - Gustavo Chagoya
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
| | - Galal Elsayed
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
| | - Houman Sotoudeh
- Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA.
| | - William Stetler
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
| | - Gregory K Friedman
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
- Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA.
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Lowder 512, 1600 7th Avenue South, Birmingham, AL 35223, USA.
| | - Joshua D Bernstock
- Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.
- Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA.
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43
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Cox OF, Huber PW. Developing Practical Therapeutic Strategies that Target Protein SUMOylation. Curr Drug Targets 2019; 20:960-969. [PMID: 30362419 PMCID: PMC6700758 DOI: 10.2174/1389450119666181026151802] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 01/02/2023]
Abstract
Post-translational modification by small ubiquitin-like modifier (SUMO) has emerged as a global mechanism for the control and integration of a wide variety of biological processes through the regulation of protein activity, stability and intracellular localization. As SUMOylation is examined in greater detail, it has become clear that the process is at the root of several pathologies including heart, endocrine, and inflammatory disease, and various types of cancer. Moreover, it is certain that perturbation of this process, either globally or of a specific protein, accounts for many instances of congenital birth defects. In order to be successful, practical strategies to ameliorate conditions due to disruptions in this post-translational modification will need to consider the multiple components of the SUMOylation machinery and the extraordinary number of proteins that undergo this modification.
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Affiliation(s)
- Olivia F. Cox
- Department of Chemistry and Biochemistry, Harper Cancer Research Institute, Center for Stem Cells and Regenerative Medicine, University of Notre Dame Notre Dame, Indiana 46556, U.S.A
| | - Paul W. Huber
- Department of Chemistry and Biochemistry, Harper Cancer Research Institute, Center for Stem Cells and Regenerative Medicine, University of Notre Dame Notre Dame, Indiana 46556, U.S.A
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44
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Zhou M, Lin F, Xu W, Jin R, Xu A. Decreased SUMOylation of the retinoblastoma protein in keratinocytes during the pathogenesis of vitiligo. Mol Med Rep 2018; 18:3469-3475. [PMID: 30066925 DOI: 10.3892/mmr.2018.9299] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 03/12/2018] [Indexed: 11/06/2022] Open
Abstract
The role of SUMOylation in the pathogenesis of vitiligo has not been reported previously. The present study aimed to reveal abnormalities in small ubiquitin‑like modifier (SUMO) conjugation in keratinocytes from depigmented lesions of patients with vitiligo and confirm the role of SUMOylation in keratinocytes from patients with vitiligo. Skin samples used for immunohistochemistry were obtained by punch biopsy from the depigmented lesions of 6 patients. Blisters were produced by vacuum and the roofs were collected for keratinocyte culture. HaCaT cells were transduced with SUMO1 knockdown vectors. The protein expression of SUMO1, SUMO‑specific peptidase 1 (SENP1), ubiquitin‑conjugating enzyme E2 I (Ubc9), SUMO‑activating enzyme subunit 1 (SAE1), cyclin‑dependent kinase (CDK)2, CDK6, proliferating cell nuclear antigen (PCNA), retinoblastoma protein (Rb), phosphorylated Rb (pRb) and β‑actin was assessed by western blotting. The SUMOylation status of proteins was assessed by immunoprecipitation. Cell cycle analysis was performed by flow cytometry and cell proliferation rate was investigated using a Cell Counting Kit‑8. The results demonstrated that the levels of SUMO1‑conjugated proteins were decreased in vitiligo lesions and vitiligo keratinocytes compared with normal controls. The protein expression of Ubc9 was decreased and SENP1 was increased in vitiligo keratinocytes compared with normal keratinocytes, with no alterations in SAE1 expression. Following knockdown of SUMO1 in HaCaT cells, the proliferation of HaCaT cells was reduced and the cell cycle was arrested in G1 phase. Furthermore, the protein expression levels of PCNA, CDK2, CDK6 and pRb were reduced in SUMO1‑knockdown HaCaT cells, and SUMOylated Rb was also decreased markedly in keratinocytes from lesions of patients with vitiligo compared with normal keratinocytes. In conclusion, vitiligo lesions in the present study exhibited dysregulated SUMOylation and deSUMOylation balance and dysregulation of cell cycle progression may be present in SUMO1 knockdown HaCaT cells. These results indicate that deSUMOylation of Rb of keratinocytes may serve an important role in vitiligo, providing a novel direction for the study into the mechanism of vitiligo.
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Affiliation(s)
- Miaoni Zhou
- Department of Dermatology, Hangzhou Institute of Dermatology and Venereology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China
| | - Fuquan Lin
- Department of Dermatology, Hangzhou Institute of Dermatology and Venereology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China
| | - Wen Xu
- Department of Dermatology, Hangzhou Institute of Dermatology and Venereology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China
| | - Rong Jin
- Department of Dermatology, Hangzhou Institute of Dermatology and Venereology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China
| | - Aie Xu
- Department of Dermatology, Hangzhou Institute of Dermatology and Venereology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China
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Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. J Transl Med 2018; 98:799-813. [PMID: 29472640 PMCID: PMC6397426 DOI: 10.1038/s41374-018-0035-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 12/27/2017] [Accepted: 01/10/2018] [Indexed: 11/08/2022] Open
Abstract
The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.
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Abstract
Post-translational modification of substrate proteins by SUMO conjugation regulates a diverse array of cellular processes. While predominantly a nuclear protein modification, there is a growing appreciation that SUMOylation of proteins outside the nucleus plays direct roles in controlling synaptic transmission, neuronal excitability, and adaptive responses to cell stress. Furthermore, alterations in protein SUMOylation are observed in a wide range of neurological and neurodegenerative diseases, and several extranuclear disease-associated proteins have been shown to be directly SUMOylated. Here, focusing mainly on SUMOylation of synaptic and mitochondrial proteins, we outline recent developments and discoveries, and present our opinion as to the most exciting avenues for future research to define how SUMOylation of extranuclear proteins regulates neuronal and synaptic function.
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Affiliation(s)
- Jeremy M Henley
- School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK.
| | - Ruth E Carmichael
- School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK
| | - Kevin A Wilkinson
- School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK.
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Guber RD, Schindler AB, Budron MS, Chen KL, Li Y, Fischbeck KH, Grunseich C. Nucleocytoplasmic transport defect in a North American patient with ALS8. Ann Clin Transl Neurol 2018; 5:369-375. [PMID: 29560381 PMCID: PMC5846449 DOI: 10.1002/acn3.515] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 11/27/2017] [Accepted: 11/29/2017] [Indexed: 01/26/2023] Open
Abstract
Amyotrophic lateral sclerosis 8 (ALS8) is a rare progressive neurodegenerative disease resulting from mutation in the gene for vesicle-associated membrane protein-associated protein B. We evaluated a North American patient using exome sequencing, and identified a P56S mutation. The disease protein had similar subcellular localization and expression levels in the patient and control fibroblasts. Patient fibroblasts showed increased basal endoplasmic reticulum stress and dysfunction of nucleocytoplasmic transport as evidenced by impaired Ran trafficking. This finding extends the identification of ALS8 into North America, and indicates a cellular defect similar to other forms of hereditary motor neuron disease.
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Affiliation(s)
- Robert D Guber
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
| | - Alice B Schindler
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
| | - Maher S Budron
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
| | - Ke-Lian Chen
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
| | - Yuebing Li
- Neuromuscular Center Cleveland Clinic 9500 Euclid Avenue Cleveland Ohio 44195
| | - Kenneth H Fischbeck
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
| | - Christopher Grunseich
- Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH 35 Convent Drive Bethesda Maryland 20892
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48
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Bernstock JD, Yang W, Ye DG, Shen Y, Pluchino S, Lee YJ, Hallenbeck JM, Paschen W. SUMOylation in brain ischemia: Patterns, targets, and translational implications. J Cereb Blood Flow Metab 2018; 38:5-16. [PMID: 29148315 PMCID: PMC5757445 DOI: 10.1177/0271678x17742260] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia.
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Affiliation(s)
- Joshua D Bernstock
- 1 Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA.,2 Department of Clinical Neurosciences, Division of Stem Cell Neurobiology, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Wei Yang
- 3 Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Daniel G Ye
- 1 Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - Yuntian Shen
- 3 Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Stefano Pluchino
- 2 Department of Clinical Neurosciences, Division of Stem Cell Neurobiology, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Yang-Ja Lee
- 1 Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - John M Hallenbeck
- 1 Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, MD, USA
| | - Wulf Paschen
- 3 Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.,4 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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Morris JR, Garvin AJ. SUMO in the DNA Double-Stranded Break Response: Similarities, Differences, and Cooperation with Ubiquitin. J Mol Biol 2017; 429:3376-3387. [PMID: 28527786 DOI: 10.1016/j.jmb.2017.05.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/12/2017] [Accepted: 05/12/2017] [Indexed: 10/19/2022]
Abstract
In recent years, our knowledge of the varied role that ubiquitination plays in promoting signal amplification, novel protein interactions, and protein turnover has progressed rapidly. This is particularly remarkable in the examination of how DNA double-stranded breaks (DSBs) are repaired, with many components of the ubiquitin (Ub) conjugation, de-conjugation, and recognition machinery now identified as key factors in DSB repair. In addition, a member of the Ub-like family, small Ub-like modifier (SUMO), has also been recognised as integral for efficient repair. Here, we summarise our emerging understanding of SUMOylation both as a distinct modification and as a cooperative modification with Ub, using the cellular response to DNA DSBs as the primary setting to compare these modifications.
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Affiliation(s)
- Joanna R Morris
- Birmingham Centre for Genome Biology and Institute of Cancer and Genomics, Medical and Dental School, University of Birmingham, Edgbaston, B15 2TT, UK.
| | - Alexander J Garvin
- Birmingham Centre for Genome Biology and Institute of Cancer and Genomics, Medical and Dental School, University of Birmingham, Edgbaston, B15 2TT, UK
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Peters M, Wielsch B, Boltze J. The role of SUMOylation in cerebral hypoxia and ischemia. Neurochem Int 2017; 107:66-77. [DOI: 10.1016/j.neuint.2017.03.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/09/2017] [Accepted: 03/15/2017] [Indexed: 10/19/2022]
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