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

Zachary T. Spencer, Victoria H. Ng, Hassina Benchabane, Ghalia Saad Siddiqui, Deepesh Duwadi, Ben Maines, Jamal M. Bryant, Anna Schwarzkopf, Kai Yuan, Sara N. Kassel, Anant Mishra, Ashley Pimentel, Andres M. Lebensohn, Rajat Rohatgi, Scott A. Gerber, David J. Robbins, Ethan Lee () and Yashi Ahmed ()
Additional contact information
Zachary T. Spencer: Dartmouth College
Victoria H. Ng: Vanderbilt University
Hassina Benchabane: Dartmouth College
Ghalia Saad Siddiqui: Dartmouth College
Deepesh Duwadi: Dartmouth College
Ben Maines: Dartmouth College
Jamal M. Bryant: Vanderbilt University
Anna Schwarzkopf: Vanderbilt University
Kai Yuan: Dartmouth College
Sara N. Kassel: Vanderbilt University
Anant Mishra: Dartmouth College
Ashley Pimentel: Dartmouth College
Andres M. Lebensohn: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Rajat Rohatgi: Stanford University School of Medicine
Scott A. Gerber: Geisel School of Medicine at Dartmouth
David J. Robbins: Georgetown University
Ethan Lee: Vanderbilt University
Yashi Ahmed: Dartmouth College

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41843-0

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