Abstract
The Tcf/Lef family of transcription factors mediates the Wnt/β-catenin pathway that is involved in a wide range of biological processes, including vertebrate embryogenesis and diverse pathogenesis. Post-translational modifications, including phosphorylation, sumoylation and acetylation, are known to be important for the regulation of Tcf/Lef proteins. However, the importance of ubiquitination and ubiquitin-mediated regulatory mechanisms for Tcf/Lef activity are still unclear. Here, we newly show that ubiquitin C-terminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt signalling. Biochemical analyses demonstrated that deubiquitinating activity of Uch37 is not involved in Tcf7 protein stability but is required for the association of Tcf7 to target gene promoter in both Xenopus embryo and human liver cancer cells. In vivo analyses further revealed that Uch37 functions as a positive regulator of the Wnt/β-catenin pathway downstream of β-catenin stabilization that is required for the expression of ventrolateral mesoderm genes during Xenopus gastrulation. Our study provides a new mechanism for chromatin occupancy of Tcf7 and uncovers the physiological significance of Uch37 during early vertebrate development by regulating the Wnt/β-catenin pathway.
Highlights
Ubiquitin C-terminal hydrolase 37 (Uch37) is a deubiquitinating enzyme (DUB) that is functionally linked to multiple protein complexes[11,12,13]
We identified Uch[37] as a novel positive regulator of Wnt signalling and revealed the detailed molecular mechanism regulating Wnt signalling in Xenopus embryos
Our study shows that Uch[37] is a bona fide DUB for Tcf[7] by directly removing polyubiquitin chains from Tcf[7]
Summary
Ubiquitin C-terminal hydrolase 37 (Uch37) is a deubiquitinating enzyme (DUB) that is functionally linked to multiple protein complexes[11,12,13]. It was suggested that Uch[37] regulates genome integrity and gene transcription in the nucleus. Nuclear Uch[37] mediates DNA double-strand breaks (DSBs) repair by stabilizing the nuclear factor related to κB-binding protein (NFRKB), a subunit of the INO80 chromatin remodelling complex[17]. We report that Uch[37] mediates the deubiquitination of Tcf[7] without affecting protein stability. We suggest that enzymatic activity of Uch[37] is required for DNA binding of Tcf[7] in Xenopus gastrula embryo and human liver cancer cells. Our in vivo analyses reveal that Uch[37] acts as a positive regulator of the Wnt/β-catenin pathway by regulating the expression of ventrolateral mesoderm genes during Xenopus gastrulation
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