Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state.
Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state.
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DOI：
10.7554/elife.58537
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发表时间：
2020-10-28
期刊：
影响因子：
7.7
通讯作者：
Compton AA
中科院分区：
文献类型：
--
作者：
Rahman K;Coomer CA;Majdoul S;Ding SY;Padilla-Parra S;Compton AA
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.
