1. Cell Biology
  2. Developmental Biology
Download icon

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
Research Article
  • Cited 0
  • Views 232
  • Annotations
Cite this article as: eLife 2020;9:e56793 doi: 10.7554/eLife.56793

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.

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)

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

  • 232
    Page views
  • 61
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Cell Biology
    Kanji Okumoto et al.
    Research Article Updated

    Most of peroxisomal matrix proteins including a hydrogen peroxide (H2O2)-decomposing enzyme, catalase, are imported in a peroxisome-targeting signal type-1 (PTS1)-dependent manner. However, little is known about regulation of the membrane-bound protein import machinery. Here, we report that Pex14, a central component of the protein translocation complex in peroxisomal membrane, is phosphorylated in response to oxidative stresses such as H2O2 in mammalian cells. The H2O2-induced phosphorylation of Pex14 at Ser232 suppresses peroxisomal import of catalase in vivo and selectively impairs in vitro the interaction of catalase with the Pex14-Pex5 complex. A phosphomimetic mutant Pex14-S232D elevates the level of cytosolic catalase, but not canonical PTS1-proteins, conferring higher cell resistance to H2O2. We thus suggest that the H2O2-induced phosphorylation of Pex14 spatiotemporally regulates peroxisomal import of catalase, functioning in counteracting action against oxidative stress by the increase of cytosolic catalase.

    1. Cell Biology
    Natalia Felipe-Medina et al.
    Research Article Updated

    Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.