Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1 alpha
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Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1a is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1 alpha signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1 alpha with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1 alpha oligomerization. The regulation of IRE1 alpha signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1 alpha signaling by fine-tuning the threshold to engage an adaptive UPR.
FONDECYT 1140549 3130365 3150113 3160461 FONDAP program 15150012 Millennium Institute P09-015-F European Commission RD MSCA-RISE 734749 Michael J. Fox Foundation for Parkinson's Research Target Validation grant 9277 FONDEF ID16I10223 D11E1007 US Office of Naval Research Global N62909-16-1-2003 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 ALSRP Therapeutic Idea Award AL150111 Muscular Dystrophy Association 382453 CONICYT-Brazil 441921/2016-7 CONICYT Ph.D. fellowship 21130169 Canadian Institutes of Health research grants MOP-15291 MOP-15415 MOP-53050 INSERM Societe Francophone du Diabete (SFD/MSD) Societe Francaise d'Hepatologie (AFEF/Aptalis) La Ligue contre le Cancer (BMM) French government (National Research Agency, ANR) "Investments for the Future'' LABEX SIGNALIFE ANR-11-LABX-002801 German Research Foundation (DFG) GO 1987/2-1 BNI-P09015F
Artículo de publicación ISI
Quote ItemMolecular Cell 69, 238–252 (2018)