Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1 alpha

Abstract

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.