title: Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival.
abstract: Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2α, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Saveljeva
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cleary
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mnich
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Abiodun
authors.initials: A
authors.lastname: Ayo
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pakos-Zebrucka
authors.affiliation: MannKind Corporation, Valencia, California, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Patterson
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Logue
authors.affiliation: Apoptosis Research Centre, NUI Galway, Ireland.|School of Natural Sciences, NUI Galway, Ireland.
authors.forename: Afshin
authors.initials: A
authors.lastname: Samali
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D000084622:Sestrins
chemical_list: D004722:Endoribonucleases; D000076222:Mechanistic Target of Rapamycin Complex 1; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C465398:SESN2 protein, human; D000084622:Sestrins; C000605543:XBP1 protein, human; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human
keywords: ER stress; SESTRIN 2; UPR; autophagy; cell death