2. Academic Validation
  3. Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress

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

  • EMBO J. 2020 May 18;39(10):e103841. doi: 10.15252/embj.2019103841.
Jiaojiao Yu # 1 2,  Tao Li # 1 2,  Yu Liu 3,  Xi Wang 1,  Jianchao Zhang 1 2,  Xi'e Wang 1,  Guizhi Shi 4,  Jizhong Lou 2 5,  Likun Wang 1 2,  Chih-Chen Wang 1 2,  Lei Wang 1 2
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 3 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 4 Laboratory Animal Center of Institute of Biophysics, Chinese Academy of Sciences, Aviation General Hospital of Beijing, University of Chinese Academy of Sciences, Beijing, China.
  • 5 Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • # Contributed equally.
PMID: 32149426 DOI: 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 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.

Keywords

Fam20C; IRE1α; endoplasmic reticulum; phosphorylation; protein disulfide isomerase.

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