PMID- 35535673
OWN - NLM
STAT- MEDLINE
DCOM- 20221213
LR  - 20221213
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 21
IP  - 6
DP  - 2022 Jun
TI  - Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated 
      antioxidative response.
PG  - e13616
LID - 10.1111/acel.13616 [doi]
LID - e13616
AB  - Accumulation of oxidative stress is highly intertwined with aging process and 
      contributes to aging-related diseases, such as neurodegenerative diseases. 
      Deciphering the molecular machinery that regulates oxidative stress is 
      fundamental to further uncovering the pathogenesis of these diseases. 
      Chaperone-mediated autophagy (CMA), a highly selective lysosome-dependent 
      degradation process, has been proven to be an important maintainer of cellular 
      homeostasis through multiple mechanisms, one of which is the attenuation of 
      oxidative stress. However, the specific mechanisms underlying this antioxidative 
      action of CMA are not fully understood. In this study, we found that CMA directly 
      degrades Kelch-like ECH-associated protein 1 (Keap1), an adaptor of E3 ligase 
      complex that promotes the degradation of nuclear factor erythroid 2-related 
      factor 2 (Nrf2), which is a master transcriptional regulator in antioxidative 
      response. Activated CMA induced by prolonged oxidative stress led to an increase 
      in Nrf2 level by effectively degrading Keap1, contributing to Nrf2 nuclear 
      translocation and the expression of multiple downstream antioxidative genes. 
      Meanwhile, together with previous study showing that Nrf2 can also 
      transcriptionally regulate LAMP2A, the rate-limiting factor of CMA process, we 
      reveal a feed-forward loop between CMA and Nrf2. Our study identifies CMA as a 
      previously unrecognized regulator of Keap1-Nrf2 pathway and reinforces the 
      antioxidative role of CMA.
CI  - (c) 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Zhu, Lin
AU  - Zhu L
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - He, Shulei
AU  - He S
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Huang, Lu
AU  - Huang L
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Ren, Dongni
AU  - Ren D
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Nie, Tiejian
AU  - Nie T
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Tao, Kai
AU  - Tao K
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Xia, Li
AU  - Xia L
AD  - Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu 
      Hospital, Fourth Military Medical University, Xi'an, China.
FAU - Lu, Fangfang
AU  - Lu F
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
FAU - Mao, Zixu
AU  - Mao Z
AD  - Departments of Pharmacology and Chemical Biology, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Yang, Qian
AU  - Yang Q
AUID- ORCID: 0000-0001-5986-2682
AD  - Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220510
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Antioxidants)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Antioxidants/pharmacology
MH  - Autophagy
MH  - *Chaperone-Mediated Autophagy
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - Oxidative Stress
PMC - PMC9197408
OTO - NOTNLM
OT  - 6-OHDA
OT  - CMA
OT  - Keap1-Nrf2 pathway
OT  - oxidative stress
COIS- All authors declare no competing interests.
EDAT- 2022/05/11 06:00
MHDA- 2022/06/18 06:00
PMCR- 2022/06/01
CRDT- 2022/05/10 05:53
PHST- 2022/03/01 00:00 [revised]
PHST- 2020/04/23 00:00 [received]
PHST- 2022/04/04 00:00 [accepted]
PHST- 2022/05/11 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2022/05/10 05:53 [entrez]
PHST- 2022/06/01 00:00 [pmc-release]
AID - ACEL13616 [pii]
AID - 10.1111/acel.13616 [doi]
PST - ppublish
SO  - Aging Cell. 2022 Jun;21(6):e13616. doi: 10.1111/acel.13616. Epub 2022 May 10.