Study on the ubiquitination of Tcf7 for Wnt signaling during Xenopus embryogenesis

Abstract

The Tcf/Lef family of transcription factors mediates Wnt/ß-catenin signaling, which is involved in a wide range of biological processes such as vertebrate embryogenesis, cell proliferation, tissue homeostasis and diverse pathogeneses. Post-translational modifications, including phosphorylation, sumoylation and acetylation have been suggested as an important regulatory mechanism for transcriptional activity of Tcf/Lef family. However, the ubiquitination-mediated Tcf/Lef regulation is still unclear. In this study, I newly report that ubiquitin Cterminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt/ß-catenin signaling. Biochemical analyses demonstrated that Uch37 modulates polyubiquitination of Tcf7 protein, which has a non-proteolytic function. In addition, the deubiquitinating activity of Uch37 is required for the association of Tcf7 to the target gene promoter in both Xenopus and human liver cancer cells. In vivo analyses using Xenopus embryo further revealed that Uch37 functions as a positive regulator of the Wnt/ß-catenin signaling downstream of the ß-catenin stabilization required for the expression of ventrolateral mesoderm genes during Xenopus gastrulation. This 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/ß-catenin pathway.