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Feng J, Chen W, Li S, Fang Q, Chen X, Bai G, Tian M, Huang Y, Xu P, Wang Z, Ma Y. PACAP ameliorates obesity-induced insulin resistance through FAIM/Rictor/AKT axis. FEBS J 2024; 291:4096-4110. [PMID: 39041617 DOI: 10.1111/febs.17228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/17/2024] [Accepted: 07/05/2024] [Indexed: 07/24/2024]
Abstract
Obesity and obesity-related insulin resistance have been a research hotspot. Pituitary adenylate cyclase activating polypeptide (PACAP) has emerged as playing a significant role in energy metabolism, holding promising potential for attenuating insulin resistance. However, the precise mechanism is not fully understood. Palmitic acid and a high-fat diet (HFD) were used to establish insulin resistance model in Alpha mouse liver 12 cell line and C57BL/6 mice, respectively. Subsequently, we assessed the effects of PACAP both in vivo and in vitro. Lentivirus vectors were used to explore the signaling pathway through which PACAP may ameliorate insulin resistance. PACAP was found to selectively bind to the PACAP type I receptor receptor and ameliorate insulin resistance, which was characterized by increased glycogen synthesis and the suppression of gluconeogenesis in the insulin-resistant cell model and HFD-fed mice. These effects were linked to the activation of the Fas apoptotic inhibitory molecule/rapamycin-insensitive companion of mammalian target of rapamycin/RAC-alpha serine/threonine-protein kinase (FAIM/Rictor/AKT) axis. Furthermore, PACAP ameliorated insulin resistance by increasing solute carrier family 2, facilitated glucose transporter members 2/4 and inhibiting gluconeogenesis-related proteins glucose 6-phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 2 expression. Meanwhile, the phosphorylation of hepatic AKT/glycogen synthase kinase 3β was promoted both in vivo and in vitro by PACAP. Additionally, PACAP treatment decreased body weight, food intake and blood glucose levels in obese mice. Our study shows that PACAP ameliorated insulin resistance through the FAIM/Rictor/AKT axis, presenting it as a promising drug candidate for the treatment of obesity-related insulin resistance.
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Affiliation(s)
- Jia Feng
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Wenhui Chen
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shanshan Li
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Qianchen Fang
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xingwu Chen
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Ge Bai
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Meng Tian
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yongmei Huang
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Pei Xu
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zixian Wang
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yi Ma
- Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- The National Demonstration Center for Experimental Education of Life Science and Technology, Jinan University, Guangzhou, China
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Li Y, Ruan GX, Chen W, Huang H, Zhang R, Wang J, Ouyang Y, Zhu Z, Meng L, Wang R, Huo J, Xu S, Ou X. The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation. FEBS Lett 2023; 597:1748-1760. [PMID: 37171241 DOI: 10.1002/1873-3468.14633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/13/2023]
Abstract
Naïve B cells become activated and differentiate into antibody-secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain-containing adapter protein with coiled-coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell-specific Wac knockout mice have severely compromised T cell-dependent and -independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac-deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac-mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.
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Affiliation(s)
- Yuxing Li
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Gui-Xin Ruan
- Medical School, Taizhou University, Zhejiang, China
| | - Wenjing Chen
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Hengjun Huang
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Rui Zhang
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Jing Wang
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Yu Ouyang
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Zhijian Zhu
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Limin Meng
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Ruisi Wang
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Jianxin Huo
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore City, Singapore
| | - Shengli Xu
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore City, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xijun Ou
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
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Tan I, Xu S, Huo J, Huang Y, Lim HH, Lam KP. Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response. J Biol Chem 2023; 299:104906. [PMID: 37302555 PMCID: PMC10404683 DOI: 10.1016/j.jbc.2023.104906] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/13/2023] Open
Abstract
The tumor suppressor Liver Kinase B1 (LKB1) is a multifunctional serine/threonine protein kinase that regulates cell metabolism, polarity, and growth and is associated with Peutz-Jeghers Syndrome and cancer predisposition. The LKB1 gene comprises 10 exons and 9 introns. Three spliced LKB1 variants have been documented, and they reside mainly in the cytoplasm, although two possess a nuclear-localization sequence (NLS) and are able to shuttle into the nucleus. Here, we report the identification of a fourth and novel LKB1 isoform that is, interestingly, targeted to the mitochondria. We show that this mitochondria-localized LKB1 (mLKB1) is generated from alternative splicing in the 5' region of the transcript and translated from an alternative initiation codon encoded by a previously unknown exon 1b (131 bp) hidden within the long intron 1 of LKB1 gene. We found by replacing the N-terminal NLS of the canonical LKB1 isoform, the N-terminus of the alternatively spliced mLKB1 variant encodes a mitochondrial transit peptide that allows it to localize to the mitochondria. We further demonstrate that mLKB1 colocalizes histologically with mitochondria-resident ATP Synthase and NAD-dependent deacetylase sirtuin-3, mitochondrial (SIRT3) and that its expression is rapidly and transiently upregulated by oxidative stress. We conclude that this novel LKB1 isoform, mLKB1, plays a critical role in regulating mitochondrial metabolic activity and oxidative stress response.
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Affiliation(s)
- Ivan Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Shengli Xu
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jianxin Huo
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Yuhan Huang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Hong-Hwa Lim
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
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Luo W, Dai J, Liu J, Huang Y, Zheng Z, Xu P, Ma Y. PACAP attenuates hepatic lipid accumulation through the FAIM/AMPK/IRβ axis during overnutrition. Mol Metab 2022; 65:101584. [PMID: 36055580 PMCID: PMC9478455 DOI: 10.1016/j.molmet.2022.101584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/23/2022] [Accepted: 08/25/2022] [Indexed: 11/12/2022] Open
Abstract
Objective Pituitary adenylate cyclase-activating polypeptide (PACAP) was reported to attenuate hepatic lipid accumulation in overnutrition-related metabolic disorder, mediated by up-regulation of fas apoptosis inhibitory molecule (FAIM). However, how PACAP regulates FAIM in metabolic tissues remains to be addressed. Here we investigated the underlying mechanism on the role of PACAP in ameliorating metabolic disorder and examined the potential therapeutic effects of PACAP in preventing the progression of metabolic associated fatty liver disease (MAFLD). Methods Mouse models with MAFLD induced by high-fat diet were employed. Different doses of PACAP were intraperitoneally administrated. Western blot, luciferase assay, lentiviral-mediated gene manipulations and animal metabolic phenotyping analysis were performed to explore the signaling pathway involved in PACAP function. Results PACAP ameliorated the excessive hepatic lipid accumulation and inhibited lipogenesis in HFD-fed C57BL/6J mice. Mechanistically, PACAP activated the FAIM-AMPK-IRβ axis to inhibit the expression of lipid synthesis genes, and FAIM mediated the effects of PACAP. FAIM suppression via lentiviral-mediated shRNA inhibited the activation of AMPK, whereas FAIM overexpression promoted AMPK activation. PACAP increased the promoter activity of FAIM gene through activating PKA-CREB signaling pathway. Conclusion Our work demonstrated that the administration of PACAP represented a feasible approach for treating hepatic lipid accumulation in MAFLD. The findings reveal the molecular mechanism that PACAP increase FAIM expression and activates the FAIM/AMPK/IRβ signaling axis, thus inhibits lipogenesis to mediate its beneficial effects.
PACAP ameliorates hepatic lipid accumulation through the AMPK pathway. AMPK is a downstream mediator of FAIM. FAIM is transcriptionally activated by CREB and regulated by PACAP. PACAP regulates the FAIM-AMPK-IRβ axis to treat fatty liver phenotype.
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Affiliation(s)
- Wei Luo
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Jiaxin Dai
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Jianmin Liu
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Yongmei Huang
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Ziqiong Zheng
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Pei Xu
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Yi Ma
- Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.
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5
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Picarda E, Galbo PM, Zong H, Rajan MR, Wallenius V, Zheng D, Börgeson E, Singh R, Pessin J, Zang X. The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development. SCIENCE ADVANCES 2022; 8:eabm7012. [PMID: 35476450 PMCID: PMC9045715 DOI: 10.1126/sciadv.abm7012] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 03/11/2022] [Indexed: 05/09/2023]
Abstract
The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.
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Affiliation(s)
- Elodie Picarda
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Phillip M. Galbo
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Haihong Zong
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Meenu Rohini Rajan
- Institute of Medicine, Department of Molecular and Clinical Medicine, The Wallenberg Laboratory and Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Ville Wallenius
- Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Emma Börgeson
- Institute of Medicine, Department of Molecular and Clinical Medicine, The Wallenberg Laboratory and Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Physiology, Region Vaestra Goetaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Rajat Singh
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jeffrey Pessin
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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6
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Coccia E, Solé M, Comella JX. FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function. Front Cell Dev Biol 2022; 9:826037. [PMID: 35083225 PMCID: PMC8784879 DOI: 10.3389/fcell.2021.826037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Apoptosis is crucial for the correct development of the nervous system. In adulthood, the same protein machinery involved in programmed cell death can control neuronal adaptiveness through modulation of synaptic pruning and synaptic plasticity processes. Caspases are the main executioners in these molecular pathways, and their strict regulation is essential to perform neuronal remodeling preserving cell survival. FAIM-L and SIVA-1 are regulators of caspase activation. In this review we will focus on FAIM-L and SIVA-1 as two functional antagonists that modulate non-apoptotic caspase activity in neurons. Their participation in long-term depression and neurite pruning will be described in base of the latest studies performed. In addition, the association of FAIM-L non-apoptotic functions with the neurodegeneration process will be reviewed.
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Affiliation(s)
- Elena Coccia
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica I Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Montse Solé
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica I Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Joan X Comella
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica I Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
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Han T, Wang P, Wang Y, Xun W, Lei J, Wang T, Lu Z, Gan M, Zhang W, Yu B, Wang JB. FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma. Autophagy 2021; 18:1416-1432. [PMID: 34720024 PMCID: PMC9225548 DOI: 10.1080/15548627.2021.1987672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Altered glutamine metabolism is an important aspect of cancer metabolic reprogramming. The GLS isoform GAC (glutaminase C), the rate-limiting enzyme in glutaminolysis, plays a vital role in cancer initiation and progression. Our previous studies demonstrated that phosphorylation of GAC was essential for its high enzymatic activity. However, the molecular mechanisms for GAC in maintaining its high enzymatic activity and protein stability still need to be further clarified. FAIM/FAIM1 (Fas apoptotic inhibitory molecule) is known as an important anti-apoptotic protein, but little is known about its function in tumorigenesis. Here, we found that knocking down FAIM induced macroautophagy/autophagy through suppressing the activation of the MTOR pathway in lung adenocarcinoma. Further studies demonstrated that FAIM could promote the tetramer formation of GAC through increasing PRKCE/PKCε-mediated phosphorylation. What's more, FAIM also stabilized GAC through sequestering GAC from degradation by protease ClpXP. These effects increased the production of α-ketoglutarate, leading to the activation of MTOR. Besides, FAIM also promoted the association of ULK1 and MTOR and this further suppressed autophagy induction. These findings discovered new functions of FAIM and elucidated an important molecular mechanism for GAC in maintaining its high enzymatic activity and protein stability.
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Affiliation(s)
- Tianyu Han
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, P.R.China
| | - Pengcheng Wang
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
| | - Yanan Wang
- School of Life Sciences, Nanchang University, Nanchang, P. R.China
| | - Wenze Xun
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
| | - Jiapeng Lei
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
| | - Tao Wang
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
| | - Zhuo Lu
- School of Life Sciences, Nanchang University, Nanchang, P. R.China
| | - Mingxi Gan
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
| | - Wei Zhang
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, P.R.China
| | - Bentong Yu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R.China
| | - Jian-Bin Wang
- School of Basic Medical Sciences, Nanchang University, Nanchang, P. R.China
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8
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Sirés A, Turch-Anguera M, Bogdanov P, Sampedro J, Ramos H, Ruíz Lasa A, Huo J, Xu S, Lam KP, López-Soriano J, Pérez-García MJ, Hernández C, Simó R, Solé M, Comella JX. Faim knockout leads to gliosis and late-onset neurodegeneration of photoreceptors in the mouse retina. J Neurosci Res 2021; 99:3103-3120. [PMID: 34713467 DOI: 10.1002/jnr.24978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 08/13/2021] [Accepted: 09/21/2021] [Indexed: 01/08/2023]
Abstract
Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim-/- ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR. Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim-/- mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation. These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.
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Affiliation(s)
- Anna Sirés
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Mireia Turch-Anguera
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.,Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Joel Sampedro
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Agustín Ruíz Lasa
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Research Center and Memory Clinic. Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
| | - Jianxin Huo
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Shengli Xu
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Joaquín López-Soriano
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - M Jose Pérez-García
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Montse Solé
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Joan X Comella
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.,Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
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9
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Liu G, Jia L, Shao Q, Lu H, Zhao J, Yin J. MicroRNA profiling of Neospora caninum tachyzoites (NC-1) using a high-throughput approach. Parasitol Res 2021; 120:2165-2174. [PMID: 33893549 DOI: 10.1007/s00436-021-07155-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 04/05/2021] [Indexed: 02/05/2023]
Abstract
Neospora caninum is an important pathogen commonly causing spontaneous abortion in livestock. The parasite is known to remain in cysts in an inactive state; or it can undergo expansive development within an intermediate host. However, the mechanisms that trigger the proliferation of N. caninum have not been thoroughly elucidated. For various organisms, it has been demonstrated that microRNAs (miRNAs) can act as important endogenous regulatory factors in gene regulation during cell differentiation and development. However, miRNAs and their function have not been studied in N. caninum. In this study, small RNA libraries from N. caninum tachyzoites (NC-1 strain) were analyzed using a high-throughput RNA sequencing technology combined with systematic bioinformatics analysis. A considerable number of novel miRNAs from N. caninum NC-1 strain tachyzoites were identified. Of the 300 miRNAs found by bioinformatics analysis, 10 were conserved miRNAs belonging to 10 metazoan miRNA families, while 290 were novel miRNAs. The expression of 13 novel miRNAs was verified by real-time quantitative PCR (qRT-PCR). Data from this study provided and identified authentic miRNAs for the first time in N. caninum. The study also introduces a framework for further investigations of RNAi-dependent regulatory mechanisms of the parasite and provides data for further understanding of N. caninum development.
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Affiliation(s)
- Gang Liu
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis/College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Lijun Jia
- Laboratory of Veterinary Microbiology, Department of Veterinary Medicine, Yanbian University, Yanji, 133002, China
| | - Qingyan Shao
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis/College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Huijun Lu
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis/College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Jixue Zhao
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Jigang Yin
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis/College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
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10
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Coccia E, Masanas M, López-Soriano J, Segura MF, Comella JX, Pérez-García MJ. FAIM Is Regulated by MiR-206, MiR-1-3p and MiR-133b. Front Cell Dev Biol 2021; 8:584606. [PMID: 33425889 PMCID: PMC7785887 DOI: 10.3389/fcell.2020.584606] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/27/2020] [Indexed: 12/17/2022] Open
Abstract
Apoptosis plays an important role during development, control of tissue homeostasis and in pathological contexts. Apoptosis is executed mainly through the intrinsic pathway or the death receptor pathway, i.e., extrinsic pathway. These processes are tightly controlled by positive and negative regulators that dictate pro- or anti-apoptotic death receptor signaling. One of these regulators is the Fas Apoptotic Inhibitory Molecule (FAIM). This death receptor antagonist has two main isoforms, FAIM-S (short) which is the ubiquitously expressed, and a longer isoform, FAIM-L (long), which is mainly expressed in the nervous system. Despite its role as a death receptor antagonist, FAIM also participates in cell death-independent processes such as nerve growth factor-induced neuritogenesis or synaptic transmission. Moreover, FAIM isoforms have been implicated in blocking the formation of protein aggregates under stress conditions or de-regulated in certain pathologies such as Alzheimer’s and Parkinson’s diseases. Despite the role of FAIM in physiological and pathological processes, little is known about the molecular mechanisms involved in the regulation of its expression. Here, we seek to investigate the post-transcriptional regulation of FAIM isoforms by microRNAs (miRNAs). We found that miR-206, miR-1-3p, and miR-133b are direct regulators of FAIM expression. These findings provide new insights into the regulation of FAIM and may provide new opportunities for therapeutic intervention in diseases in which the expression of FAIM is altered.
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Affiliation(s)
- Elena Coccia
- Cell Signaling and Apoptosis Group, Vall d'Hebron Research Institute, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Marc Masanas
- Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Joaquín López-Soriano
- Cell Signaling and Apoptosis Group, Vall d'Hebron Research Institute, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Miguel F Segura
- Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Joan X Comella
- Cell Signaling and Apoptosis Group, Vall d'Hebron Research Institute, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - M José Pérez-García
- Cell Signaling and Apoptosis Group, Vall d'Hebron Research Institute, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
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11
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Wang P, Xun W, Han T, Cheng Z. FAIM-S functions as a negative regulator of NF-κB pathway and blocks cell cycle progression in NSCLC cells. Cell Cycle 2020; 19:3458-3467. [PMID: 33249986 DOI: 10.1080/15384101.2020.1843811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Tumorigenesis is closely related to the disorder of the cell cycle. The cell cycle progression includes the interphase (G0/G1, S, and G2 phase) and mitosis (M phase). CCND1 is a key protein that regulates the entry of the G0/G1 phase into the S phase. In our study, we found that the short form of Fas Apoptosis Inhibitory Molecule 1 (FAIM-S) could regulate the expression of CCND1 and had a tumor-suppressing role in non-small cell lung cancer (NSCLC). Overexpressing FAIM-S significantly inhibited the proliferation and cell cycle progression in NSCLC cells. Further studies demonstrated that FAIM-S could interact with IKK-α, reducing its protein stability. This effect led to the suppression of the NF-κB pathway, resulting in the decreased expression of CCND1. Thus, our study demonstrated that FAIM-S functioned as a negative regulator of the NF-κB pathway and played a tumor-suppressing role through blocking cell cycle progression in NSCLC cells.
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Affiliation(s)
- Pengcheng Wang
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China.,Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Wenze Xun
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Tianyu Han
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Zhujun Cheng
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
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12
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Zhang Q, Cai Z, Lhomme M, Sahana G, Lesnik P, Guerin M, Fredholm M, Karlskov-Mortensen P. Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels. Sci Rep 2020; 10:18434. [PMID: 33116219 PMCID: PMC7595098 DOI: 10.1038/s41598-020-75612-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022] Open
Abstract
Dyslipidemia is the primary cause of cardiovascular disease, which is a serious human health problem in large parts of the world. Therefore, it is important to understand the genetic and molecular mechanisms that regulate blood levels of cholesterol and other lipids. Discovery of genetic elements in the regulatory machinery is often based on genome wide associations studies (GWAS) focused on end-point phenotypes such as total cholesterol level or a disease diagnosis. In the present study, we add endophenotypes, such as serum levels of intermediate metabolites in the cholesterol synthesis pathways, to a GWAS analysis and use the pig as an animal model. We do this to increase statistical power and to facilitate biological interpretation of results. Although the study population was limited to ~ 300 individuals, we identify two genome-wide significant associations and ten suggestive associations. Furthermore, we identify 28 tentative associations to loci previously associated with blood lipids or dyslipidemia associated diseases. The associations with endophenotypes may inspire future studies that can dissect the biological mechanisms underlying these previously identified associations and add a new level of understanding to previously identified associations.
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Affiliation(s)
- Qianqian Zhang
- Bioinformatics Research Centre (BiRC), Aarhus University, C.F.Møllers Allé 8, 8000, Aarhus C, Denmark
| | - Zexi Cai
- Center for Quantitativ Genetics and Genomics, Aarhus University, Blichers Allé 20, 8830, Tjele, Danmark
| | - Marie Lhomme
- ICANalytics, Institute of Cardiometabolism and Nutrition (ICAN), 47-83 boulevard de l'hôpital, 75013, Paris, France
| | - Goutam Sahana
- Center for Quantitativ Genetics and Genomics, Aarhus University, Blichers Allé 20, 8830, Tjele, Danmark
| | - Philippe Lesnik
- Unité de Recherche sur les maladies cardiovasculaires, le métabolisme et la nutrition, INSERM UMR_S 1166, ICAN Institute of Cardiometabolism & Nutrition, Faculté de Médecine Sorbonne Université, Sorbonne Université, 4ème étage, Bureau 421,91, boulevard de l'Hôpital, 75634, Paris Cedex 13, France
| | - Maryse Guerin
- Unité de Recherche sur les maladies cardiovasculaires, le métabolisme et la nutrition, INSERM UMR_S 1166, ICAN Institute of Cardiometabolism & Nutrition, Faculté de Médecine Sorbonne Université, Sorbonne Université, 4ème étage, Bureau 421,91, boulevard de l'Hôpital, 75634, Paris Cedex 13, France
| | - Merete Fredholm
- Animal Genetics, Bioinformatics and Breeding, Department of Veterinary and Animal Sciences, University of Copenhagen, Gronnegaardsvej 3, 1870, Frederikgsberg C, Denmark
| | - Peter Karlskov-Mortensen
- Animal Genetics, Bioinformatics and Breeding, Department of Veterinary and Animal Sciences, University of Copenhagen, Gronnegaardsvej 3, 1870, Frederikgsberg C, Denmark.
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13
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Kaku H, Rothstein TL. FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates. Front Mol Biosci 2020; 7:32. [PMID: 32175331 PMCID: PMC7056718 DOI: 10.3389/fmolb.2020.00032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 02/11/2020] [Indexed: 11/13/2022] Open
Abstract
A key element of cellular homeostasis lies in the way in which misfolded and dysfunctional proteins are handled. Cellular pathways that include proteasomal destruction and autophagic disposal are components of normal proteostasis. Here we report a novel molecule that plays a non-redundant role in maintaining homeostasis, Fas Apoptosis Inhibitory Molecule (FAIM). FAIM is highly conserved throughout evolution and bears no homology to any other protein. We found that FAIM counteracts heat and oxidative stress-induced loss of cell viability. FAIM is recruited to ubiquitinated proteins induced by cellular stress and the levels of stress-induced protein aggregates are much greater in FAIM-deficient cell lines. Primary fibroblasts from FAIM-deficient mice showed the same proteostasis deficits as cell lines. Administration of a mediator of oxidative stress to FAIM-deficient animals induced more ubiquitinated protein aggregates and more organ damage as compared to wild type mice. These results identify a completely new actor that protects cells against stress-induced loss of viability by preventing protein aggregation.
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Affiliation(s)
- Hiroaki Kaku
- Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States.,Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States
| | - Thomas L Rothstein
- Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States.,Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States
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14
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Xiao X, Qiu P, Gong H, Chen X, Sun Y, Hong A, Ma Y. PACAP ameliorates hepatic metabolism and inflammation through up-regulating FAIM in obesity. J Cell Mol Med 2019; 23:5970-5980. [PMID: 31270932 PMCID: PMC6714231 DOI: 10.1111/jcmm.14453] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 04/15/2019] [Accepted: 05/15/2019] [Indexed: 11/29/2022] Open
Abstract
Obesity is considered a chronic inflammatory disease, the inflammatory factors, such as interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and small inducible cytokine A5 (RANTES), are elevated in obese individuals. Pituitary adenylate cyclase-activating polypeptide (PACAP) suppresses anti-inflammatory cytokines and ameliorates glucose and lipid metabolism. Our previous study showed that Fas apoptosis inhibitory molecule (FAIM) is a new mediator of Akt2 signalling, increases the insulin signalling pathway and lipid metabolism. In this study, we found that PACAP promoted the expression of FAIM protein in a human hepatocyte cell line (L02). Overexpression of FAIM with lentivirus suppressed the expression of the inflammatory factor interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and tumour necrosis factor alpha (TNF-α). Following treatment of obese mice with FAIM or PACAP for 2 weeks, inflammation was alleviated and the bodyweight and blood glucose levels were decreased. Overexpression of FAIM down-regulated the expression of adipogenesis proteins, including SREBP1, SCD1, FAS, SREBP2 and HMGCR, and up-regulated glycogen synthesis proteins, including Akt2 (Ser474) phosphorylation, GLUT2 and GSK-3β, in the liver of obese mice. However, down-regulation of FAIM with shRNA promotes obesity. Altogether, our data identified that FAIM mediates the function of PACAP in anti-inflammation, glucose regulation and lipid metabolism in obese liver.
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Affiliation(s)
- Xing Xiao
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - Pei Qiu
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - Hui‐Zhen Gong
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - Xue‐Ming Chen
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - Yan Sun
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - An Hong
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
| | - Yi Ma
- Department of Cellular Biology, Institute of Biomedicine, National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong ProvinceJinan UniversityGuangzhouGuangdongPeople's Republic of China
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15
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Huo J, Xu S, Lam KP. FAIM: An Antagonist of Fas-Killing and Beyond. Cells 2019; 8:cells8060541. [PMID: 31167518 PMCID: PMC6628066 DOI: 10.3390/cells8060541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
Fas Apoptosis Inhibitory Molecule (FAIM) is an anti-apoptotic protein that is up-regulated in B cell receptor (BCR)-activated B cells and confers upon them resistance to Fas-mediated cell death. Faim has two alternatively spliced isoforms, with the short isoform ubiquitously expressed in various tissues and the long isoform mainly found in the nervous tissues. FAIM is evolutionarily conserved but does not share any significant primary sequence homology with any known protein. The function of FAIM has been extensively studied in the past 20 years, with its primary role being ascribed to be anti-apoptotic. In addition, several other functions of FAIM were also discovered in different physiological and pathological conditions, such as cell growth, metabolism, Alzheimer’s disease and tumorigenesis. However, the detailed molecular mechanisms underlying FAIM’s role in these conditions remain unknown. In this review, we summarize comprehensively the functions of FAIM in these different contexts and discuss its potential as a diagnostic, prognostic or therapeutic target.
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Affiliation(s)
- Jianxin Huo
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
| | - Shengli Xu
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
| | - Kong-Peng Lam
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
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16
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Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24:2661-2672. [PMID: 29991872 PMCID: PMC6034146 DOI: 10.3748/wjg.v24.i25.2661] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/04/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomohiro Kaneko
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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17
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Candi E, Tesauro M, Cardillo C, Lena AM, Schinzari F, Rodia G, Sica G, Gentileschi P, Rovella V, Annicchiarico-Petruzzelli M, Di Daniele N, Melino G. Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome. Biochem J 2018; 475:1019-1035. [PMID: 29437994 DOI: 10.1042/bcj20170604] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 01/30/2018] [Accepted: 01/31/2018] [Indexed: 12/15/2022]
Abstract
Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic-vascular complications of obesity and may lead to the development of innovative targeted therapies.
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Affiliation(s)
- Eleonora Candi
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy
- Biochemistry Laboratory, Istituto Dermopatico Immacolata (IDI-IRCCS), 00100 Rome, Italy
| | - Manfredi Tesauro
- Department of Systems Medicine, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | - Carmine Cardillo
- Department of Internal Medicine, Catholic University, 00168 Rome, Italy
| | - Anna Maria Lena
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | | | - Giuseppe Rodia
- Department of Systems Medicine, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | - Giuseppe Sica
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | - Paolo Gentileschi
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | - Valentina Rovella
- Department of Systems Medicine, University of Rome 'Tor Vergata', 00133 Rome, Italy
| | | | - Nicola Di Daniele
- Department of Systems Medicine, University of Rome 'Tor Vergata', 00133 Rome, Italy melino@uniroma2
| | - Gerry Melino
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy
- Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, PO Box 138, Leicester LE1 9HN, U.K
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Identification and characterization of new isoforms of human fas apoptotic inhibitory molecule (FAIM). PLoS One 2017; 12:e0185327. [PMID: 28981531 PMCID: PMC5628826 DOI: 10.1371/journal.pone.0185327] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 09/11/2017] [Indexed: 01/07/2023] Open
Abstract
Fas Apoptosis Inhibitory Molecule (FAIM) is an evolutionarily highly conserved death receptor antagonist, widely expressed and known to participate in physiological and pathological processes. Two FAIM transcript variants have been characterized to date, namely FAIM short (FAIM-S) and FAIM long (FAIM-L). FAIM-S is ubiquitously expressed and serves as an anti-apoptotic protein in the immune system. Furthermore, in neurons, this isoform promotes NGF-induced neurite outgrowth through NF-кB and ERK signaling. In contrast FAIM-L is found only in neurons, where it exerts anti-apoptotic activity against several stimuli. In addition to these two variants, in silico studies point to the existence of two additional isoforms, neither of which have been characterized to date. In this regard, here we confirm the presence of these two additional FAIM isoforms in human fetal brain, fetal and adult testes, and placenta tissues. We named them FAIM-S_2a and FAIM-L_2a since they have the same sequence as FAIM-S and FAIM-L, but include exon 2a. PCR and western blot revealed that FAIM-S_2a shows ubiquitous expression in all the tissues and cellular models tested, while FAIM-L_2a is expressed exclusively in tissues of the nervous system. In addition, we found that, when overexpressed in non-neuronal cells, the splicing factor nSR100 induces the expression of the neuronal isoforms, thus identifying it as responsible for the generation of FAIM-L and FAIM-L_2a. Functionally, FAIM-S_2a and FAIM-L_2a increased neurite outgrowth in response to NGF stimulation in a neuronal model. This observation thus, supports the notion that these two isoforms are involved in neuronal differentiation. Furthermore, subcellular fractionation experiments revealed that, in contrast to FAIM-S and FAIM-L, FAIM-S_2a and FAIM-L_2a are able to localize to the nucleus, where they may have additional functions. In summary, here we report on two novel FAIM isoforms that may have relevant roles in the physiology and pathology of the nervous system.
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Planells-Ferrer L, Urresti J, Coccia E, Galenkamp KMO, Calleja-Yagüe I, López-Soriano J, Carriba P, Barneda-Zahonero B, Segura MF, Comella JX. Fas apoptosis inhibitory molecules: more than death-receptor antagonists in the nervous system. J Neurochem 2016; 139:11-21. [DOI: 10.1111/jnc.13729] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/14/2016] [Accepted: 07/02/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Laura Planells-Ferrer
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Jorge Urresti
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Elena Coccia
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Koen M. O. Galenkamp
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Isabel Calleja-Yagüe
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Joaquín López-Soriano
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Paulina Carriba
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Bruna Barneda-Zahonero
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Miguel F. Segura
- Group of Translational Research in Childhood and Adolescent Cancer; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
| | - Joan X. Comella
- Cell Signaling and Apoptosis Group; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR); Barcelona Spain
- Institut de Neurociències; Departament de Bioquímica i Biologia Molecular; Facultat de Medicina; Universitat Autònoma de Barcelona; Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
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