Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state

  1. Kazi Rahman
  2. Charles A Coomer
  3. Saliha Majdoul
  4. Selena Y Ding
  5. Sergi Padilla-Parra
  6. Alex A Compton  Is a corresponding author
  1. National Cancer Institute, United States
  2. King's College London, United Kingdom

Abstract

The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline rich transmembrane protein 2 (PRRT2), a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 (and to a lesser extent, glycine-91) disrupted IFITM3 oligomerization and reduced its antiviral activity against Influenza A virus. An oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent and amphipathic helix-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Kazi Rahman

    HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2986-0007
  2. Charles A Coomer

    HIV Dynamics and Replication Program, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Saliha Majdoul

    HIV Dynamics and Replication Program, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0530-6354
  4. Selena Y Ding

    HIV Dynamics and Replication Program, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4413-644X
  5. Sergi Padilla-Parra

    Department of Infectious Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8010-9481
  6. Alex A Compton

    HIV Dynamics and Replication Program, National Cancer Institute, Frederick, United States
    For correspondence
    alex.compton@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7508-4953

Funding

National Institutes of Health (Intramural Research Program)

  • Kazi Rahman
  • Charles A Coomer
  • Saliha Majdoul
  • Selena Y Ding
  • Alex A Compton

European Research Council (ERC-2019-CoG-863869 FUSION)

  • Sergi Padilla-Parra

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

Reviewing Editor

  1. Mark Marsh, University Coillege London, United Kingdom

Publication history

  1. Received: May 4, 2020
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: October 28, 2020 (version 1)
  4. Version of Record published: November 13, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Kazi Rahman
  2. Charles A Coomer
  3. Saliha Majdoul
  4. Selena Y Ding
  5. Sergi Padilla-Parra
  6. Alex A Compton
(2020)
Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state
eLife 9:e58537.
https://doi.org/10.7554/eLife.58537
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