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

  1. Author:
    Rahman,Kazi [ORCID]
    Coomer, Charles A
    Majdoul,Saliha [ORCID]
    Ding, Selena Y [ORCID]
    Padilla-Parra, Sergi [ORCID]
    Compton,Alex [ORCID]

  2. Author Address

    HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, United States., HIV Dynamics and Replication Program, National Cancer Institute, Frederick, United States., Department of Infectious Diseases, King 39;s College London, London, United Kingdom.,
    1. Year: 2020
    2. Date: Oct 28
    3. Epub Date: 2020 10 28
  2. Journal: eLife
    1. 9
    2. Pages: pii: e58537
  4. Type of Article: Article
  5. Article Number: e58537
  6. ISSN: 2050-084X
  1. 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.

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External Sources

  1. View Full Text
  2. DOI: 10.7554/eLife.58537
  3. PMID: 33112230
  4. View record in Web of Science®
  5. WOS: 000592693800001
  6. PII : 58537

Library Notes

  1. Fiscal Year: FY2020-2021
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