Natural mutations in IFITM3 modulate post-translational regulation and toggle antiviral specificity.
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.
Virus & Immunity Unit, Institut Pasteur, Paris, France alex.compton@pasteur.fr schwartz@pasteur.fr.
Alex A
0000-0002-7508-4953
AA
Compton
Virus & Immunity Unit, Institut Pasteur, Paris, France.
Nicolas
N
Roy
Virus & Immunity Unit, Institut Pasteur, Paris, France.
Françoise
F
Porrot
Virus & Immunity Unit, Institut Pasteur, Paris, France.
Anne
A
Billet
Virus & Immunity Unit, Institut Pasteur, Paris, France.
Nicoletta
N
Casartelli
Department of Microbial Infection & Immunity, The Ohio State University, Columbus, OH, USA.
Jacob S
JS
Yount
Lady Davis Institute, McGill University, Montreal, QC, Canada.
Chen
C
Liang
Virus & Immunity Unit, Institut Pasteur, Paris, France alex.compton@pasteur.fr schwartz@pasteur.fr.|CNRS-URA 3015, Paris, France.|Vaccine Research Institute, Creteil, France.
Olivier
O
Schwartz
D000818:Animals; D002460:Cell Line; D019143:Evolution, Molecular; D016678:Genome; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007369:Interferon Inducers / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011323:Primates / Q000235:genetics*; D021381:Protein Transport / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics*; D054875:Ubiquitination / Q000235:genetics; D014780:Viruses / Q000276:immunology
C080082:IFITM3 protein, human; D007369:Interferon Inducers; D008565:Membrane Proteins; D016601:RNA-Binding Proteins
HIV; IFITM; evolution; innate immunity; virus