RRC ID 30497
Author Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, Lee HE, Kang D, Rhee SG.
Title Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage.
Journal Cell Metab
Abstract Sestrins (Sesns) protect cells from oxidative stress. The mechanism underlying the antioxidant effect of Sesns has remained unknown, however. The Nrf2-Keap1 pathway provides cellular defense against oxidative stress by controlling the expression of antioxidant enzymes. We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62-dependent autophagic degradation of Keap1. Sesn2 was upregulated in the liver of mice subjected to fasting or subsequent refeeding with a high-carbohydrate, fat-free diet, whereas only refeeding promoted Keap1 degradation and Nrf2 activation, because only refeeding induced p62 expression. Ablation of Sesn2 blocked Keap1 degradation and Nrf2 activation induced by refeeding and thereby increased the susceptibility of the liver to oxidative damage resulting from the acute stimulation of lipogenesis associated with refeeding.
Volume 17(1)
Pages 73-84
Published 2013-1-8
DOI 10.1016/j.cmet.2012.12.002
PII S1550-4131(12)00493-7
PMID 23274085
MeSH Adaptor Proteins, Signal Transducing / metabolism* Animals Autophagy Carrier Proteins / metabolism Cell Cycle Proteins / metabolism Cytoskeletal Proteins / metabolism* HCT116 Cells HEK293 Cells HeLa Cells Humans Kelch-Like ECH-Associated Protein 1 Liver / metabolism* Liver / physiopathology Male Mice Mice, Inbred C57BL NF-E2-Related Factor 2 / metabolism* Nuclear Proteins Oxidative Stress Peroxidases Protein Binding Proteins / metabolism* Transcription Factor TFIIH Transcription Factors / metabolism* Transfection Up-Regulation
IF 21.567
Times Cited 223
Mice RBRC01390