Journal
EMBO JOURNAL
Volume 39, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019103841
Keywords
endoplasmic reticulum; Fam20C; IRE1 alpha; phosphorylation; protein disulfide isomerase
Categories
Funding
- National Key R&D Program of China [2016YFA0500200, 2017YFA0504000]
- National Natural Science Foundation of China [31771261, 31571163, 31870761, 31770877, 11672317]
- Strategic Priority Research Program of CAS [XDB37020303]
- Youth Innovation Promotion Association, CAS
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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.
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