Journal article
Protein Disulfide Isomerase A6 Controls the Decay of IRE1 alpha Signaling via Disulfide-Dependent Association
Molecular cell, v 53(4), pp 562-576
20 Feb 2014
PMID: 24508390
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 1 alpha (IRE1 alpha). A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1 alpha 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 IRE1 alpha 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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Details
- Title
- Protein Disulfide Isomerase A6 Controls the Decay of IRE1 alpha Signaling via Disulfide-Dependent Association
- Creators
- Davide Eletto - Children's Hospital of PhiladelphiaDaniela Eletto - Children's Hospital of PhiladelphiaDevin Dersh - Children's Hospital of PhiladelphiaTali Gidalevitz - Drexel UniversityYair Argon - Children's Hospital of Philadelphia
- Publication Details
- Molecular cell, v 53(4), pp 562-576
- Publisher
- Elsevier
- Number of pages
- 15
- Grant note
- T32GM008275 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01AG018001 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) P40OD010440 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P40 OD010440; AI-18001; GM-77480 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000331660200006
- Scopus ID
- 2-s2.0-84894236302
- Other Identifier
- 991019167535504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology