Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor by the HECT E3Â Ubiquitin Ligase Hyd/UBR5.
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.
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
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
Mol. Cell
Date: Jul. 20, 2017
PubMed ID: 28689657
View in: Pubmed Google Scholar
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