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.

细胞外信号通过与增强子复合物结合以操作转录开关的效应器转导到细胞核。例如，Wnt 增强体是一种多蛋白复合物，通过 T 细胞因子 (TCF) 与 Wnt 响应增强子相关，并通过 Groucho/TLE 共阻遏物保持沉默。 Wnt 激活的 β-连环蛋白与 TCF 结合以克服这种抑制，但其如何实现这一点尚不清楚。在这里，我们发现这个过程依赖于 HECT E3 泛素连接酶 Hyd/UBR5，它是果蝇和人类细胞系激活的犰狳/β-连环蛋白下游的 Wnt 信号反应所必需的。我们将 Groucho/TLE 确定为功能相关底物，UBR5 对其进行泛素化是由 Wnt 信号传导诱导并由 β-catenin 赋予。 UBR5 依赖性泛素化导致 TLE 失活还涉及 VCP/p97，这是一种调节各种细胞底物（包括泛素化染色质蛋白）折叠的 AAA ATP 酶。因此，Hyd/UBR5 对 Groucho/TLE 的泛素化是犰狳/β-连环蛋白激活转录的关键先决条件。