Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor by the HECT E3 Ubiquitin Ligase Hyd/UBR5

Mol Cell. 2017 Jul 20;67(2):181-193.e5. doi: 10.1016/j.molcel.2017.06.009. Epub 2017 Jul 6.

Abstract

Extracellular signals are transduced to the cell nucleus by effectors that bind to enhancer complexes to operate transcriptional switches. For example, the Wnt enhanceosome is a multiprotein complex associated with Wnt-responsive enhancers through T cell factors (TCF) and kept silent by Groucho/TLE co-repressors. Wnt-activated β-catenin binds to TCF to overcome this repression, but how it achieves this is unknown. Here, we discover that this process depends on the HECT E3 ubiquitin ligase Hyd/UBR5, which is required for Wnt signal responses in Drosophila and human cell lines downstream of activated Armadillo/β-catenin. We identify Groucho/TLE as a functionally relevant substrate, whose ubiquitylation by UBR5 is induced by Wnt signaling and conferred by β-catenin. Inactivation of TLE by UBR5-dependent ubiquitylation also involves VCP/p97, an AAA ATPase regulating the folding of various cellular substrates including ubiquitylated chromatin proteins. Thus, Groucho/TLE ubiquitylation by Hyd/UBR5 is a key prerequisite that enables Armadillo/β-catenin to activate transcription.

Keywords: Groucho/TLE repression; HECT E3 ubiquitin ligase; VCP/p97; Wnt/β-catenin signaling.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Animals, Genetically Modified
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • CRISPR-Cas Systems
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Proteolysis
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Activation
  • Transfection
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Valosin Containing Protein
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • ARM protein, Drosophila
  • Armadillo Domain Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • Co-Repressor Proteins
  • Drosophila Proteins
  • Repressor Proteins
  • TLE3 protein, human
  • Transcription Factors
  • beta Catenin
  • gro protein, Drosophila
  • UBR5 protein, human
  • hyd protein, Drosophila
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • ter94 protein, Drosophila