Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

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 IRE1a signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1a with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1a oligomerization. The regulation of IRE1a 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 IRE1a signaling by fine-tuning the threshold to engage an adaptive UPR.

Sepulveda D, Rojas-Rivera D, Rodrà­guez DA, Groenendyk J, Köhler A, Lebeaupin C, Ito S, Urra H, Carreras-Sureda A, Hazari Y, Vasseur-Cognet M, Ali MMU, Chevet E, Campos G, Godoy P, Vaisar T, Bailly-Maitre B, Nagata K, Michalak M, Sierralta J, Hetz C.

Molecular Cell (Mol Cell)

enero 10, 2018

DOI: 10.1016/j.molcel.2017.12.028

Investigador BNI: Jimena Sierralta , Claudio Hetz