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.

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.

Metrics

  • 2,770
    views
  • 384
    downloads
  • 53
    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. 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

Share this article

https://doi.org/10.7554/eLife.58537

Further reading

    1. Evolutionary Biology
    Matthew Osmond, Graham Coop
    Research Article

    Spatial patterns in genetic diversity are shaped by individuals dispersing from their parents and larger-scale population movements. It has long been appreciated that these patterns of movement shape the underlying genealogies along the genome leading to geographic patterns of isolation by distance in contemporary population genetic data. However, extracting the enormous amount of information contained in genealogies along recombining sequences has, until recently, not been computationally feasible. Here we capitalize on important recent advances in genome-wide gene-genealogy reconstruction and develop methods to use thousands of trees to estimate per-generation dispersal rates and to locate the genetic ancestors of a sample back through time. We take a likelihood approach in continuous space using a simple approximate model (branching Brownian motion) as our prior distribution of spatial genealogies. After testing our method with simulations we apply it to Arabidopsis thaliana. We estimate a dispersal rate of roughly 60km2 per generation, slightly higher across latitude than across longitude, potentially reflecting a northward post-glacial expansion. Locating ancestors allows us to visualize major geographic movements, alternative geographic histories, and admixture. Our method highlights the huge amount of information about past dispersal events and population movements contained in genome-wide genealogies.

    1. Evolutionary Biology
    Mattias Siljestam, Claus Rueffler
    Research Article

    The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than ten alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognized.