Artículos de revistas
Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α
Fecha
2018Registro en:
Molecular Cell, Volumen 69, Issue 2, 2018, Pages 238-252.e7
10974164
10972765
10.1016/j.molcel.2017.12.028
Autor
Sepulveda, Denisse
Rojas Rivera, Diego
Rodríguez, Diego A.
Groenendyk, Jody
Köhler, Andres
Lebeaupin, Cynthia
Ito, Shinya
Urra, Hery
Carreras-Sureda, Amado
Hazari, Younis
Vasseur-Cognet, Mireille
Ali, Maruf M.U.
Chevet, Eric
Campos, Gisela
Godoy, Patricio
Institución
Resumen
© 2018 Elsevier Inc. Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α 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 IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α 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 IRE1α signaling by fine-tuning the threshold to eng