The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling

Victoria H. Ng, Zachary Spencer, Leif R. Neitzel, Anmada Nayak, Matthew A. Loberg, Chen Shen, Sara N. Kassel, Heather K. Kroh, Zhenyi An, Christin C. Anthony, Jamal M. Bryant, Amanda Lawson, Lily Goldsmith, Hassina Benchabane, Amanda G. Hansen, Jingjing Li, Starina D’Souza, Andres M. Lebensohn, Rajat Rohatgi, William A. Weiss, Vivian L. Weiss, Charles Williams, Charles C. Hong, David J. Robbins, Yashi Ahmed () and Ethan Lee ()
Additional contact information
Victoria H. Ng: Vanderbilt University
Zachary Spencer: Geisel School of Medicine at Dartmouth College
Leif R. Neitzel: Vanderbilt University
Anmada Nayak: Georgetown University
Matthew A. Loberg: Vanderbilt University Medical Center
Chen Shen: Georgetown University
Sara N. Kassel: Vanderbilt University
Heather K. Kroh: Vanderbilt University Medical Center
Zhenyi An: UCSF Helen Diller Family Comprehensive Cancer Center
Christin C. Anthony: Vanderbilt University
Jamal M. Bryant: Vanderbilt University
Amanda Lawson: Vanderbilt University
Lily Goldsmith: Vanderbilt University
Hassina Benchabane: Geisel School of Medicine at Dartmouth College
Amanda G. Hansen: Vanderbilt University
Jingjing Li: Vanderbilt University
Starina D’Souza: Vanderbilt University
Andres M. Lebensohn: National Cancer Institute, National Institutes of Health
Rajat Rohatgi: Stanford University School of Medicine
William A. Weiss: UCSF Helen Diller Family Comprehensive Cancer Center
Vivian L. Weiss: Vanderbilt University Medical Center
Charles Williams: University of Maryland School of Medicine
Charles C. Hong: University of Maryland School of Medicine
David J. Robbins: Georgetown University
Yashi Ahmed: Geisel School of Medicine at Dartmouth College
Ethan Lee: Vanderbilt University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The relative abundance of Wnt receptors plays a crucial role in controlling Wnt signaling in tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate Wnt receptors are well-characterized, the deubiquitylase that reverses these reactions remains unclear. Herein, we identify USP46, UAF1, and WDR20 (USP46 complex) as positive regulators of Wnt signaling in cultured human cells. We find that the USP46 complex is similarly required for Wnt signaling in Xenopus and zebrafish embryos. We demonstrate that Wnt signaling promotes the association between the USP46 complex and cell surface Wnt coreceptor, LRP6. Knockdown of USP46 decreases steady-state levels of LRP6 and increases the level of ubiquitylated LRP6. In contrast, overexpression of the USP46 complex blocks ubiquitylation of LRP6 by the ubiquitin ligases RNF43 and ZNFR3. Size exclusion chromatography studies suggest that the size of the USP46 cytoplasmic complex increases upon Wnt stimulation. Finally, we show that USP46 is essential for Wnt-dependent intestinal organoid viability, likely via its role in LRP6 receptor homeostasis. We propose a model in which the USP46 complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes via a pruning mechanism that removes sterically hindering ubiquitin chains.

Date: 2023
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DOI: 10.1038/s41467-023-41836-z

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