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

Kazi Rahman, Charles A. Coomer, Saliha Majdoul, Selena Ding, Sergi Padilla-Parra, Alex A. Compton

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Article numbere58537
Pages (from-to)1-43
Number of pages43
JournaleLife
Volume9
DOIs
Publication statusPublished - Oct 2020

Cite this