title: Disruption of chaperone-mediated autophagy-dependent degradation of MEF2A by oxidative stress-induced lysosome destabilization.
abstract: Oxidative stress has been implicated in both normal aging and various neurodegenerative disorders and it may be a major cause of neuronal death. Chaperone-mediated autophagy (CMA) targets selective cytoplasmic proteins for degradation by lysosomes and protects neurons against various extracellular stimuli including oxidative stress. MEF2A (myocyte enhancer factor 2A), a key transcription factor, protects primary neurons from oxidative stress-induced cell damage. However, the precise mechanisms of how the protein stability and the transcriptional activity of MEF2A are regulated under oxidative stress remain unknown. In this study, we report that MEF2A is physiologically degraded through the CMA pathway. In pathological conditions, mild oxidative stress (200 μM H 2O 2) enhances the degradation of MEF2A as well as its activity, whereas excessive oxidative stress (> 400 μM H 2O 2) disrupts its degradation process and leads to the accumulation of nonfunctional MEF2A. Under excessive oxidative stress, an N-terminal HDAC4 (histone deacetylase 4) cleavage product (HDAC4-NT), is significantly induced by lysosomal serine proteases released from ruptured lysosomes in a PRKACA (protein kinase, cAMP-dependent, catalytic, α)-independent manner. The production of HDAC4-NT, as a MEF2 repressor, may account for the reduced DNA-binding and transcriptional activity of MEF2A. Our work provides reliable evidence for the first time that MEF2A is targeted to lysosomes for CMA degradation; oxidative stress-induced lysosome destabilization leads to the disruption of MEF2A degradation as well as the dysregulation of its function. These findings may shed light on the underlying mechanisms of pathogenic processes of neuronal damage in various neurodegenerative-related diseases.
authors.affiliation: Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu China; State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, Jiangsu China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, Jiangsu China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: J David Gladstone Institute of Virology and Immunology; University of California, San Francisco, CA USA.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Fei
authors.affiliation: Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Tan
authors.affiliation: Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi, Jiangsu China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Chemical and Biological Engineering; Changsha University of Science and Technology; Changsha, Hunan China.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Tang
authors.affiliation: School of Chemical and Biological Engineering; Changsha University of Science and Technology; Changsha, Hunan China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: School of Chemical and Biological Engineering; Changsha University of Science and Technology; Changsha, Hunan China.
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, Jiangsu China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C578036:Mef2a protein, mouse; D018832:Molecular Chaperones; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: chaperone-mediated autophagy; histone deacetylase 4; myocyte enhancer factor 2A; neurodegenerative diseases; oxidative stress