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.
Copyright © 2017 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.
MeSH terms
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism
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Animals
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Animals, Genetically Modified
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Armadillo Domain Proteins / genetics
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Armadillo Domain Proteins / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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CRISPR-Cas Systems
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Co-Repressor Proteins / genetics
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Co-Repressor Proteins / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / enzymology*
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Drosophila melanogaster / genetics
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Gene Knockdown Techniques
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HCT116 Cells
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HEK293 Cells
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HeLa Cells
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Humans
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Stability
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Proteolysis
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic*
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Transcriptional Activation
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Transfection
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
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Valosin Containing Protein
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Wnt Signaling Pathway*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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ARM protein, Drosophila
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Armadillo Domain Proteins
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Basic Helix-Loop-Helix Transcription Factors
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CTNNB1 protein, human
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Cell Cycle Proteins
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Co-Repressor Proteins
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Drosophila Proteins
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Repressor Proteins
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TLE3 protein, human
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Transcription Factors
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beta Catenin
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gro protein, Drosophila
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UBR5 protein, human
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hyd protein, Drosophila
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Ubiquitin-Protein Ligases
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Adenosine Triphosphatases
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VCP protein, human
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Valosin Containing Protein
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ter94 protein, Drosophila