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oai:repisalud.isciii.es:20.500.12105/72092024-09-27T09:22:04Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Sanchez-Alvarez, Miguel author del Pozo, Miguel Angel author Bakal, Chris author 2017-11-28 Inositol Requiring Enzyme-1 (IRE1) is the most conserved transducer of the Unfolded Protein Response (UPR), a surveillance mechanism that ensures homeostasis of the endoplasmic reticulum (ER) in eukaryotes. IRE1 activation orchestrates adaptive responses, including lipid anabolism, metabolic reprogramming, increases in protein folding competency, and ER expansion/remodeling. However, we still know surprisingly little regarding the principles by which this ER transducer is deactivated upon ER stress clearance. Here we show that Protein Kinase B-mechanistic Target of Rapamycin (PKB/AKT-mTOR) signaling controls the dynamics of IRE1 deactivation by regulating ER-mitochondria physical contacts and the autophosphorylation state of IRE1. AKT-mTOR-mediated attenuation of IRE1 activity is important for ER remodelling dynamics and cell survival in the face of recursive, transient ER stress. Our observations suggest that IRE1 attenuation is an integral component of anabolic programmes regulated by AKT-mTOR. We suggest that AKT-mTOR activity is part of a 'timing mechanism' to deactivate IRE1 immediately following engagement of the UPR, in order to limit prolonged IRE1 RNAse activity that could lead to damaging inflammation or apoptosis. Sci Rep. 2017; 7(1):16497 10.1038/s41598-017-16662-1 2045-2322 2045-2322 Scientific reports 29184100 http://hdl.handle.net/20.500.12105/7209 AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts