Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of keap1 and prevent oxidative liver damage

Soo Han Bae, Su Haeng Sung, Sue Young Oh, Jung Mi Lim, Se Kyoung Lee, Young Nyun Park, Hye Eun Lee, Dongmin Kang, Sue Goo Rhee

Research output: Contribution to journalArticlepeer-review

343 Scopus citations

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.

Original languageEnglish
Pages (from-to)73-84
Number of pages12
JournalCell Metabolism
Volume17
Issue number1
DOIs
StatePublished - 8 Jan 2013

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