Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress.

The EMBO Journal
Jiaojiao YuLei Wang

Abstract

Accumulated unfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR) to increase ER protein folding capacity. ER proteostasis and UPR signaling need to be regulated in a precise and timely manner. Here, we identify phosphorylation of protein disulfide isomerase (PDI), one of the most abundant and critical folding catalysts in the ER, as an early event during ER stress. The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1α activation and liver damage under acute ER stress. We conclude that the Fam20C-PDI axis constitutes a post-translational response to maintain ER proteostasis and plays a vital role in protecting against ER stress-induced cell death.

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Citations

Aug 14, 2020·Journal of Cell Science·Hery UrraClaudio Hetz
Dec 11, 2020·Experimental Cell Research·Madison T Wright, Lars Plate
Nov 7, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Lei WangChih-Chen Wang
Mar 7, 2021·International Journal of Molecular Sciences·Juncheng Wei, Deyu Fang
Feb 24, 2021·Nature Reviews. Cardiology·Jun RenYingmei Zhang
Mar 25, 2021·The Journal of Biological Chemistry·Carolyn A WorbySourav Banerjee
Mar 21, 2021·Cancer Medicine·Lauren E Powell, Paul A Foster
Mar 12, 2021·Endocrine Reviews·Amir AjoolabadyJun Ren
Jun 2, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Jonas HonerLucía F Zacchi
Jun 3, 2021·Mucosal Immunology·Eva ClootsMichael J Grey
Jun 3, 2021·Antioxidants & Redox Signaling·Vishwanath JhaJaehyung Cho
Aug 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xinxin ChenLei Wang
Aug 8, 2021·International Journal of Molecular Sciences·Icela Palma-LaraCarmen Palacios-Reyes

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