Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage
Open accessAbstract
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.
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Transgenic mice deficient in Sens2 and Sens3 genes have demonstrated the important role of these proteins in the suppression of age and obesity-associated mitochondrial disorders.
“transgenic mice deficient in Sens2 and Sens3 genes have demonstrated the important role of these proteins in the suppression of age and obesity-associated mitochondrial disorders (Bae et al., 2013; Lee et al., 2012).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Bae et al., 2013
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- Authors
- Bae, S. H., Sung, S. H., Oh, S. Y., Lim, J. M., Lee, S. K., Park, Y. N., Lee, H. E., Kang, D., & Rhee, S. G.
- Affiliations
- Ewha Womans University (KR)
- Yonsei University (KR)
- Corresponding author
- Bae, Soo Han
- Rhee, Sue Goo
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 17
- Issue
- 1
- Pages
- 73-84
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2057762456
- Cited by
- 492
- References
- 34
- Citations by year
- 2026: 20 · 2025: 36 · 2024: 26 · 2023: 36 · 2022: 44 · 2021: 59 · 2020: 57 · 2019: 40 · 2018: 30 · 2017: 30 · 2016: 37 · 2015: 35 · 2014: 28 · 2013: 12
- FWCI
- 9.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- RIKEN
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- sestrins, SESN1, Sestrin2, Nrf2, Keap1, p62, autophagy, RBX1, oxidative stress, liver, refeeding, fasting, lipogenesis, antioxidant defense, oxidative liver damage
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Sestrins, Animals, Autophagy, Carrier Proteins, Cytoskeletal Proteins, HeLa Cells, Humans, Liver, Male, Mice, Inbred C57BL, Nuclear Proteins, Peroxidases, Protein Binding, Proteins, Transcription Factors, Transfection, Up-Regulation, Oxidative Stress, Cell Cycle Proteins, HCT116 Cells, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice, Transcription Factor TFIIH, HEK293 Cells
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