ERAD-dependent control of the Wnt secretory factor Evi

EMBO J. 2018 Feb 15;37(4):e97311. doi: 10.15252/embj.201797311. Epub 2018 Jan 29.


Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β-catenin by the ubiquitin-proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)-associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP-dependent manner. Ubiquitination of Evi involves the E2-conjugating enzyme UBE2J2 and the E3-ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD-dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

Keywords: CGRRF1; Evi/Wls/GPR177; Porcn; Wnt signaling; regulatory ERAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / genetics
  • Acyltransferases / metabolism
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Cells, Cultured
  • Colon / metabolism*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Endoplasmic Reticulum-Associated Degradation*
  • Gene Expression Regulation*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Signal Transduction
  • Ubiquitin / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination
  • Valosin Containing Protein / genetics
  • Valosin Containing Protein / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*


  • Membrane Proteins
  • Ubiquitin
  • Wnt Proteins
  • Acyltransferases
  • PORCN protein, human
  • Ubiquitin-Conjugating Enzymes
  • VCP protein, human
  • Valosin Containing Protein