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USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling

Abstract The tumour suppressors RNF43 and ZNRF3 play a central role in development and tissue homeostasis by promoting the turnover of the Wnt receptors LRP6 and Frizzled (FZD). The stem cell growth factor R-spondin induces auto-ubiquitination and membrane clearance of ZNRF3/RNF43 to promote Wnt sig...

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Main Authors: Giebel, Nicole (Author) , Jaime-Soguero, Anchel de (Author) , García del Arco, Ana (Author) , Landry, Jonathan (Author) , Tietje, Marlene (Author) , Villacorta, Laura (Author) , Benes, Vladimir (Author) , Fernández-Sáiz, Vanesa (Author) , Acebron, Sergio P. (Author)
Format: Article (Journal)
Language:English
Published: 30 March 2021
In: EMBO reports
Year: 2021, Volume: 22, Issue: 5, Pages: 1-16
ISSN:1469-3178
DOI:10.15252/embr.202051415
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.15252/embr.202051415
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.15252/embr.202051415
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Author Notes:Nicole Giebel, Anchel de Jaime-Soguero, Ana García del Arco, Jonathan JM Landry, Marlene Tietje, Laura Villacorta, Vladimir Benes, Vanesa Fernández-Sáiz & Sergio P Acebrón
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Summary:Abstract The tumour suppressors RNF43 and ZNRF3 play a central role in development and tissue homeostasis by promoting the turnover of the Wnt receptors LRP6 and Frizzled (FZD). The stem cell growth factor R-spondin induces auto-ubiquitination and membrane clearance of ZNRF3/RNF43 to promote Wnt signalling. However, the deubiquitinase stabilising ZNRF3/RNF43 at the plasma membrane remains unknown. Here, we show that the USP42 antagonises R-spondin by protecting ZNRF3/RNF43 from ubiquitin-dependent clearance. USP42 binds to the Dishevelled interacting region (DIR) of ZNRF3 and stalls the R-spondin-LGR4-ZNRF3 ternary complex by deubiquitinating ZNRF3. Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling. Furthermore, we show that USP42 functions as a roadblock for paracrine Wnt signalling in colon cancer cells and mouse small intestinal organoids. We provide new mechanistic insights into the regulation R-spondin and conclude that USP42 is crucial for ZNRF3/RNF43 stabilisation at the cell surface.
Item Description:Gesehen am 12.01.2022
Physical Description:Online Resource
ISSN:1469-3178
DOI:10.15252/embr.202051415

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