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Flack, JE, Mieszczanek, J, Novcic, N and Bienz, M (2017) Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor by the HECT E3 Ubiquitin Ligase Hyd/UBR5. Mol. Cell 67:181-193.e5
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.
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