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EMBO J. 2018 Jul 13;37(14). pii: e98699. doi: 10.15252/embj.201798699. Epub 2018 Jun 1.

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α.

Zhang J1,2, Zhu Q3,4, Wang X1,2, Yu J1,2, Chen X1,2, Wang J5, Wang X1,2, Xiao J3,4, Wang CC1,2, Wang L6,2.

Author information

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
The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
4
Academy for Advanced Interdisciplinary Studies, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
5
Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
6
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China wanglei@moon.ibp.ac.cn.

Abstract

Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. Notably, phosphorylation of Ero1α is induced under hypoxia, reductive stress, and secretion-demanding conditions such as mammalian lactation. Collectively, our findings open a door to uncover how oxidative protein folding is regulated by phosphorylation in the secretory pathway.

KEYWORDS:

ER redox; Ero1α; Fam20C; oxidative protein folding; phosphorylation

PMID:
29858230
PMCID:
PMC6043849
[Available on 2019-07-13]
DOI:
10.15252/embj.201798699
[Indexed for MEDLINE]

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