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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase I / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Molecular Chaperones / metabolism
  • Oxidation-Reduction
  • Oxidoreductases / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Protein Transport

Substances

  • ERP44 protein, human
  • Extracellular Matrix Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Molecular Chaperones
  • ERO1A protein, human
  • Oxidoreductases
  • Casein Kinase I
  • FAM20C protein, human