PMID- 24879151
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20211021
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 10
IP  - 6
DP  - 2014 Jun
TI  - Disruption of chaperone-mediated autophagy-dependent degradation of MEF2A by 
      oxidative stress-induced lysosome destabilization.
PG  - 1015-35
LID - 10.4161/auto.28477 [doi]
AB  - 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 muM H 2O 
      2) enhances the degradation of MEF2A as well as its activity, whereas excessive 
      oxidative stress (> 400 muM 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, alpha)-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.
FAU - Zhang, Li
AU  - Zhang L
AD  - 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.
FAU - Sun, Yang
AU  - Sun Y
AD  - State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; 
      Nanjing University; Nanjing, Jiangsu China.
FAU - Fei, Mingjian
AU  - Fei M
AD  - J David Gladstone Institute of Virology and Immunology; University of California, 
      San Francisco, CA USA.
FAU - Tan, Cheng
AU  - Tan C
AD  - Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of 
      Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu 
      China.
FAU - Wu, Jing
AU  - Wu J
AD  - Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of 
      Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu 
      China.
FAU - Zheng, Jie
AU  - Zheng J
AD  - State Key Laboratory of Food Science and Technology; School of Food Science and 
      Technology; Jiangnan University; Wuxi, Jiangsu China.
FAU - Tang, Jiqing
AU  - Tang J
AD  - School of Chemical and Biological Engineering; Changsha University of Science and 
      Technology; Changsha, Hunan China.
FAU - Sun, Wei
AU  - Sun W
AD  - School of Chemical and Biological Engineering; Changsha University of Science and 
      Technology; Changsha, Hunan China.
FAU - Lv, Zhaoliang
AU  - Lv Z
AD  - School of Chemical and Biological Engineering; Changsha University of Science and 
      Technology; Changsha, Hunan China.
FAU - Bao, Jiandong
AU  - Bao J
AD  - Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of 
      Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu 
      China.
FAU - Xu, Qiang
AU  - Xu Q
AD  - State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; 
      Nanjing University; Nanjing, Jiangsu China.
FAU - Yu, Huixin
AU  - Yu H
AD  - Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of 
      Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, Jiangsu 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (MEF2 Transcription Factors)
RN  - 0 (MEF2A protein, human)
RN  - 0 (Mef2a protein, mouse)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Repressor Proteins)
RN  - EC 3.5.1.98 (HDAC4 protein, human)
RN  - EC 3.5.1.98 (Hdac5 protein, mouse)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Animals
MH  - Autophagy/genetics/*physiology
MH  - Cell Line
MH  - HEK293 Cells
MH  - Histone Deacetylases/metabolism
MH  - Humans
MH  - Lysosomes/metabolism
MH  - MEF2 Transcription Factors/genetics/metabolism
MH  - Mice
MH  - Models, Biological
MH  - Molecular Chaperones/metabolism
MH  - Neurodegenerative Diseases/etiology/metabolism/pathology
MH  - Neurons/metabolism/pathology
MH  - Oxidative Stress
MH  - Proteolysis
MH  - Repressor Proteins/metabolism
MH  - Signal Transduction
PMC - PMC4091166
OTO - NOTNLM
OT  - chaperone-mediated autophagy
OT  - histone deacetylase 4
OT  - myocyte enhancer factor 2A
OT  - neurodegenerative diseases
OT  - oxidative stress
EDAT- 2014/06/01 06:00
MHDA- 2015/05/12 06:00
PMCR- 2015/06/01
CRDT- 2014/06/01 06:00
PHST- 2014/06/01 06:00 [entrez]
PHST- 2014/06/01 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - 28477 [pii]
AID - 2012AUTO0541R3 [pii]
AID - 10.4161/auto.28477 [doi]
PST - ppublish
SO  - Autophagy. 2014 Jun;10(6):1015-35. doi: 10.4161/auto.28477.