title: The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1.
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.
authors.affiliation: Severance Biomedical Science Institute and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: rheesg@yuhs.ac.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: Severance Biomedical Science Institute and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: soohanbae@yuhs.ac.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Free radicals; Keap1; Nrf2; Sestrin; mTORC1; p62