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

Molecular cell | 2017

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.

Pubmed ID: 28689657 RIS Download

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

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