title: Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death.
abstract: Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that UPR induces Sestrin2 via ATF4 and NRF2 transcription factors and demonstrate that Sestrin2 protects cells from glucose starvation-induced cell death. Sestrin2 inactivation sensitizes cells to necroptotic cell death that is associated with a decline in ATP levels and can be suppressed by Necrostatin 7. We propose that Sestrin2 protects cells from glucose starvation-induced cell death via regulation of mitochondrial homeostasis.
authors.affiliation: Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Boxiao
authors.initials: B
authors.lastname: Ding
authors.affiliation: Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Parmigiani
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Department of Biostatistics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kellie
authors.initials: K
authors.lastname: Archer
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Budanov
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000502:physiology*; D010544:Peroxidases; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D056811:Unfolded Protein Response; D000084622:Sestrins
chemical_list: D051701:Activating Transcription Factor 4; D005947:Glucose; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D010544:Peroxidases; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C081452:Atf4 protein, mouse; C495636:Nfe2l2 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins