The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6

• Published in: Nature communications Vol. 14; no. 1; pp. 6174 - 17
• Main Authors: Spencer, Zachary T., Ng, Victoria H., Benchabane, Hassina, Siddiqui, Ghalia Saad, Duwadi, Deepesh, Maines, Ben, Bryant, Jamal M., Schwarzkopf, Anna, Yuan, Kai, Kassel, Sara N., Mishra, Anant, Pimentel, Ashley, Lebensohn, Andres M., Rohatgi, Rajat, Gerber, Scott A., Robbins, David J., Lee, Ethan, Ahmed, Yashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/51; 13/89; 13/95; 14/19; 38; 631/136/756; 631/80/86; 631/80/86/2370; 64; 64/24; 96; 96/100; 96/106; Animals; Biology; Cancer; Cell surface; CRISPR; Drosophila - genetics; Drosophila Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Inactivation; Insects; Ligands; multidisciplinary; Mutagenesis; Pattern formation; Physiology; Receptors; Science; Science (multidisciplinary); Sensitivity enhancement; Stabilization; Transcription Factors - metabolism; Tumorigenesis; Ubiquitin; Wnt protein; Wnt Signaling Pathway; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41843-0

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila . By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/β-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient. Wnt receptor levels drive signaling. Here the authors find that precise signaling in the Wnt morphogen gradient relies on Usp46, a deubiquitylase that enhances target cells sensitivity by increasing cell surface levels of the Wnt receptor Arrow/LRP6.