Wnt signaling through the Frizzled (FZD) family of serpentine receptors is essential for embryogenesis and homeostasis, and stringent control of the FZD protein level is critical for stem cell regulation. Through CRISPR/Cas9 genome-wide screening in human cells, we identified TMEM79/MATTRIN, an orphan multi-span transmembrane protein, as a specific inhibitor of Wnt/FZD signaling. TMEM79 interacts with FZD during biogenesis and promotes FZD degradation independent of ZNRF3/RNF43 ubiquitin ligases (R-spondin receptors). TMEM79 interacts with ubiquitin-specific protease 8 (USP8), whose activating mutations underlie human tumorigenesis. TMEM79 specifically inhibits USP8 deubiquitination of FZD, thereby governing USP8 substrate specificity and promoting FZD degradation. Tmem79 and Usp8 genes have a pre-bilaterian origin, and Tmem79 inhibition of Usp8 and Wnt signaling is required for anterior neural development and gastrulation in Xenopus embryos. TMEM79 is a predisposition gene for Atopic dermatitis, suggesting deregulation of Wnt/FZD signaling a possible cause for this most common yet enigmatic inflammatory skin disease.
- Xi He
- Xi He
- Xi He
- Nathalia Amado
- Jieqiong Tan
- Jose Garcia Abreu
- Xi He
- Xi He
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All Xenopus experiments were approved by Boston Children's Hospital (BCH) Institutional Animal Care and Use Committee (IACUC) and performed under protocol 18-09-3780R.
- Roel Nusse, Stanford University, United States
- Received: March 10, 2020
- Accepted: September 11, 2020
- Accepted Manuscript published: September 14, 2020 (version 1)
© 2020, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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