Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1 alpha - Archive ouverte HAL Access content directly
Journal Articles Molecular Cell Year : 2018

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1 alpha

Denisse Sepulveda
  • Function : Author
Diego Rojas-Rivera
  • Function : Author
Diego A. Rodriguez
  • Function : Author
Andres Kohler
  • Function : Author
Shinya Ito
  • Function : Author
Hery Urra
Amado Carreras-Sureda
  • Function : Author
Younis Hazari
  • Function : Author
Gisela Campos
  • Function : Author
Patricio Godoy
  • Function : Author
Tomas Vaisar
  • Function : Author
Kazuhiro Nagata
  • Function : Author
Jimena Sierralta
  • Function : Author
Claudio Hetz
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Abstract

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 engage an adaptive UPR.

Dates and versions

hal-01710048 , version 1 (15-02-2018)

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Denisse Sepulveda, Diego Rojas-Rivera, Diego A. Rodriguez, Jody Groenendyk, Andres Kohler, et al.. Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1 alpha. Molecular Cell, 2018, 69 (2), pp.238-252.e7. ⟨10.1016/j.molcel.2017.12.028⟩. ⟨hal-01710048⟩
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