Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7209
AKT-mTOR signaling modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contacts
Sanchez-Alvarez, Miguel CNIC | del Pozo, Miguel Angel CNIC | Bakal, Chris
Sci Rep. 2017; 7(1):16497
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.
This work was supported by a project grant from the Biotechnology and Biological Sciences Research Council (BB/J017183/1) and a Cancer Research UK Programme Foundation Award (C37275/1A20146) to C.Bakal; and a Spanish Ministry of Economy and Competitiveness (MINECO) project grant (SAF2014-51876-R) and a Worldwide Cancer Research Foundation project grant (15-0404) to MA del Pozo. M Sanchez-Alvarez is a CNIC IPP fellow (COFUND programme 2014). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).