Molecular Cell
Volume 53, Issue 4, 20 February 2014, Pages 562-576
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Article
Protein Disulfide Isomerase A6 Controls the Decay of IRE1α Signaling via Disulfide-Dependent Association

https://doi.org/10.1016/j.molcel.2014.01.004Get rights and content
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Highlights

  • The ER resident enzyme PDIA6 is an attenuator of the unfolded protein response

  • PDIA6 interacts covalently with cysteine 148 in the lumenal domain of activated IRE1

  • The interaction facilitates the decay of active IRE1 without affecting its onset

  • The worm ortholog of PDIA6 is an essential gene, and its loss causes excessive UPR

Summary

The response to endoplasmic reticulum (ER) stress relies on activation of unfolded protein response (UPR) sensors, and the outcome of the UPR depends on the duration and strength of signal. Here, we demonstrate a mechanism that attenuates the activity of the UPR sensor inositol-requiring enzyme 1α (IRE1α). A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine 148 in the lumenal domain of the sensor, which is oxidized when IRE1 is activated. PDIA6-deficient cells hyperrespond to ER stress with sustained autophosphorylation of IRE1α and splicing of XBP1 mRNA, resulting in exaggerated upregulation of UPR target genes and increased apoptosis. In vivo, PDIA6-deficient C. elegans exhibits constitutive UPR and fails to complete larval development, a program that normally requires the UPR. Thus, PDIA6 activity provides a mechanism that limits UPR signaling and maintains it within a physiologically appropriate range.

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These authors contributed equally to this work

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Present address: Biochemistry and Molecular Biophysics Graduate Group, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA