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The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1

Authors
 Sue Goo Rhee  ;  Soo Han Bae 
Citation
 Free Radical Biology and Medicine, Vol.88(Pt B) : 205-211, 2015 
Journal Title
 Free Radical Biology and Medicine 
ISSN
 0891-5849 
Issue Date
2015
MeSH
Animals ; Antioxidants/metabolism* ; Autophagy/physiology* ; Heat-Shock Proteins/metabolism* ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism* ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/physiology ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/metabolism*
Keywords
Autophagy ; Free radicals ; Keap1 ; Nrf2 ; Sestrin ; mTORC1 ; p62
Abstract
Sestrins 1 to 3 constitute a family of proteins that are induced in mammalian cells in response to environmental stressors. Despite their apparent lack of intrinsic catalytic antioxidant activity, Sestrins protect cells from oxidative stress by lowering intracellular levels of H2O2. Here we review the mechanisms by which various types of cellular stress induce Sestrin gene transcription as well as those underlying the antioxidant function of these proteins. Several transcriptional factors, including p53, HIF-1, FoxO, C/EBP-β, ATF4, Nrf2, and PGC-1α, contribute directly to the transcriptional activation of Sestrin genes in response to various types of stress. The antioxidant function of Sestrins is mediated by two main pathways. In one pathway, Sestrins promote the p62-dependent autophagic degradation of Keap1 and thereby upregulate Nrf2 signaling and the consequent expression of genes for antioxidant enzymes. In the second pathway, Sestrins block mTORC1 activation and thereby attenuate reactive oxygen species accumulation. This inhibition of mTORC1 activity is achieved either via the AMPK-dependent phosphorylation and activation of TSC2 and consequent inhibition of the GTPase Rheb or via inhibition of the GTPase Rag and consequent prevention of the lysosomal localization of mTORC1 triggered by amino acids. Elucidation of how these pathways operate individually or cooperatively under different stress conditions awaits further study.
Full Text
https://www.sciencedirect.com/science/article/pii/S0891584915002750
DOI
10.1016/j.freeradbiomed.2015.06.007
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Rhee, Sue Goo(이서구)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156740
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