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

Autor:	Ng VH; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.; Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA., Spencer Z; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH, 03755, USA., Neitzel LR; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA., Nayak A; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA., Loberg MA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Shen C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA., Kassel SN; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Kroh HK; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., An Z; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94158, USA., Anthony CC; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Bryant JM; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Lawson A; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Goldsmith L; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Benchabane H; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH, 03755, USA., Hansen AG; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.; STEMCELL Technologies, 1618 Station Street, Vancouver, BC, V6A 1B6, Canada., Li J; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., D'Souza S; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Lebensohn AM; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Rohatgi R; Departments of Biochemistry, Stanford University School of Medicine, Stanford, CA, 94305, USA., Weiss WA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94158, USA., Weiss VL; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Williams C; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA., Hong CC; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA., Robbins DJ; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA., Ahmed Y; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH, 03755, USA. yashi.ahmed@dartmouth.edu., Lee E; Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA. ethan.lee@vanderbilt.edu.; Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA. ethan.lee@vanderbilt.edu.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. ethan.lee@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2023 Oct 05; Vol. 14 (1), pp. 6173. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1038/s41467-023-41836-z
Abstrakt:	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. (© 2023. Springer Nature Limited.)
Databáze:	MEDLINE
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