title: Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage.
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.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea. soohanbae@ewha.ac.kr
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
authors.forename: Su Haeng
authors.initials: SH
authors.lastname: Sung
authors.forename: Sue Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Lim
authors.forename: Se Kyoung
authors.initials: SK
authors.lastname: Lee
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Dongmin
authors.initials: D
authors.lastname: Kang
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins; D018384:Oxidative Stress; D010544:Peroxidases; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D000084622:Sestrins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D010544:Peroxidases; D011506:Proteins; D051758:Transcription Factor TFIIH; D014157:Transcription Factors; C490981:Gtf2h1 protein, mouse; C117301:Keap1 protein, mouse; C540494:RBX1 protein, mouse; C531059:Sesn1 protein, mouse; D000084622:Sestrins; C529380:Sesn2 protein, mouse