Research Papers: Autophagy and Cell Death:
Endoplasmic reticulum stressmediated induction of SESTRIN 2 potentiates cell survival
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Svetlana Saveljeva1,2,*, Patricia Cleary1,2,*, Katarzyna Mnich1,2,*, Abiodun Ayo1,2, Karolina Pakos-Zebrucka1,2, John B. Patterson3, Susan E. Logue1,2,* and Afshin Samali1,2,*
1 Apoptosis Research Centre, NUI Galway, Ireland
2 School of Natural Sciences, NUI Galway, Ireland
3 MannKind Corporation, Valencia, California, USA
* These authors have contributed equally to this work
Correspondence to:
Afshin Samali, email:
Keywords: SESTRIN 2, ER stress, UPR, cell death, autophagy
Received: August 14, 2015 Accepted: January 25, 2016 Published: February 22, 2016
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.