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Natural mutations in IFITM3 modulate post‐translational regulation and toggle antiviral specificity

Abstract : The interferon-induced transmembrane (IFITM) proteins protect host cells from diverse virus infections. IFITM proteins also incorporate into HIV-1 virions and inhibit virus fusion and cell-to-cell spread, with IFITM3 showing the greatest potency. Here, we report that amino-terminal mutants of IFITM3 preventing ubiquitination and endocytosis are more abundantly incorporated into virions and exhibit enhanced inhibition of HIV-1 fusion. An analysis of primate genomes revealed that IFITM3 is the most ancient antiviral family member of the IFITM locus and has undergone a repeated duplication in independent host lineages. Some IFITM3 genes in nonhuman primates, including those that arose following gene duplication, carry amino-terminal mutations that modify protein localization and function. This suggests that "runaway" IFITM3 variants could be selected for altered antiviral activity. Furthermore, we show that adaptations in IFITM3 result in a trade-off in antiviral specificity, as variants exhibiting enhanced activity against HIV-1 poorly restrict influenza A virus. Overall, we provide the first experimental evidence that diversification of IFITM3 genes may boost the antiviral coverage of host cells and provide selective functional advantages.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-01401366
Contributor : Isma Ziani <>
Submitted on : Wednesday, November 23, 2016 - 11:27:22 AM
Last modification on : Thursday, June 18, 2020 - 12:32:05 PM

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Alex A Compton, Nicolas Roy, Françoise Porrot, Anne Billet, Nicoletta Casartelli, et al.. Natural mutations in IFITM3 modulate post‐translational regulation and toggle antiviral specificity. EMBO Reports, EMBO Press, 2016, 17 (11), pp.1657-1671. ⟨10.15252/embr.201642771⟩. ⟨pasteur-01401366⟩

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