TMEM59 potentiates Wnt signaling by promoting signalosome formation

Wnt/β-catenin signaling is crucial for adult homeostasis and stem cell maintenance, and its dysregulation is strongly associated to cancer. Upon Wnt binding, Wnt receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The assembly and regulation of these signalosomes remains largely elusive. Here, we use internally tagged Wnt ligands as a tool to isolate and analyze the composition and regulation of endogenous Wnt receptor complexes. We identify a positive regulator of Wnt signaling that facilitates signalosome formation by promoting intramembrane receptor interactions. Our results reveal that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps and involves regulated intramembrane interactions.