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.

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.

Metrics

  • 2,297
    views
  • 318
    downloads
  • 15
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.56793

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.

    1. Cell Biology
    Affiong Ika Oqua, Kin Chao ... Alejandra Tomas
    Research Article

    G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.