TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis

  1. Maorong Chen
  2. Nathalia Amado
  3. Jieqiong Tan
  4. Alice Reis
  5. Mengxu Ge
  6. Jose Garcia Abreu
  7. Xi He  Is a corresponding author
  1. F M Kirby Center, Boston Children's Hospital, Harvard Medical School, United States
  2. Universidade Federal do Rio de Janeiro, Brazil

Abstract

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.

Data availability

All datasets associated with this article are available. Source data were uploaded. Raw data for Xenopus are in the Supplementary file 1.

The following data sets were generated

Article and author information

Author details

  1. Maorong Chen

    Neurology, F M Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    Maorong Chen, M.C and X.H. through Boston Children's Hospital have filed a patent application on atopic dermatitis therapeutics Patent# WO2020069344A1..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3744-8864
  2. Nathalia Amado

    Neurology, F M Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Jieqiong Tan

    Neurology, F M Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Alice Reis

    Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    Competing interests
    No competing interests declared.
  5. Mengxu Ge

    Neurology, F M Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Jose Garcia Abreu

    Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    Competing interests
    No competing interests declared.
  7. Xi He

    Neurology, F M Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    For correspondence
    Xi.He@childrens.harvard.edu
    Competing interests
    Xi He, M.C and X.H. through Boston Children's Hospital have filed a patent application on atopic dermatitis therapeutics Patent# WO2020069344A1. X.H. is a scientific advisory board member of Leap Therapeutics, a cancer therapeutics company..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8093-7981

Funding

National Institutes of Health (R01GM126120)

  • Xi He

Boston Children's Hospital (Boston Children's Hospital (BCH) Pilot and Translational Research Program (TRP) grants)

  • Xi He

Boston Children's Hospital (BCH Intellectual and Developmental Disabilities Research Center (P30 HD-18655))

  • Xi He

Harvard Medical School (Goldenson fellowship)

  • Nathalia Amado

Chinese Scholarship Council and Central South University (visiting scholarship)

  • Jieqiong Tan

CNPq and Rio de Janeiro State Foundation for Science support

  • Jose Garcia Abreu

American Cancer Society

  • Xi He

National Institute of General Medical Sciences (R35GM134953)

  • Xi He

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Reviewing Editor

  1. Roel Nusse, Stanford University, United States

Publication history

  1. Received: March 10, 2020
  2. Accepted: September 11, 2020
  3. Accepted Manuscript published: September 14, 2020 (version 1)
  4. Version of Record published: September 28, 2020 (version 2)

Copyright

© 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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  1. Maorong Chen
  2. Nathalia Amado
  3. Jieqiong Tan
  4. Alice Reis
  5. Mengxu Ge
  6. Jose Garcia Abreu
  7. Xi He
(2020)
TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis
eLife 9:e56793.
https://doi.org/10.7554/eLife.56793

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