Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress
- 17 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 39 (10), e103841
- https://doi.org/10.15252/embj.2019103841
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 IRE1 alpha, a major UPR signal transducer, and attenuates excessive IRE1 alpha activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1 alpha 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.Funding Information
- Ministry of Science and Technology of the People's Republic of China (2016YFA0500200, 2017YFA0504000)
- National Natural Science Foundation of China (31771261, 31571163, 31870761, 31770877, 11672317)
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