title: Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals.
abstract: IFIT (interferon-induced with tetratricopeptide repeats) proteins are critical mediators of mammalian innate antiviral immunity. Mouse IFIT1 selectively inhibits viruses that lack 2'O-methylation of their mRNA 5' caps. Surprisingly, human IFIT1 does not share this antiviral specificity. Here, we resolve this discrepancy by demonstrating that human and mouse IFIT1 have evolved distinct functions using a combination of evolutionary, genetic and virological analyses. First, we show that human IFIT1 and mouse IFIT1 (renamed IFIT1B) are not orthologs, but are paralogs that diverged >100 mya. Second, using a yeast genetic assay, we show that IFIT1 and IFIT1B proteins differ in their ability to be suppressed by a cap 2'O-methyltransferase. Finally, we demonstrate that IFIT1 and IFIT1B have divergent antiviral specificities, including the discovery that only IFIT1 proteins inhibit a virus encoding a cap 2'O-methyltransferase. These functional data, combined with widespread turnover of mammalian IFIT genes, reveal dramatic species-specific differences in IFIT-mediated antiviral repertoires.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.|Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Matthew D
authors.identifier: 0000-0002-4879-9603
authors.initials: MD
authors.lastname: Daugherty
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Schaller
authors.affiliation: Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States.|Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, United States.|Department of Microbiology, University of Washington School of Medicine, Seattle, United States.|Department of Medicine, University of Washington School of Medicine, Seattle, United States.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Geballe
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.|Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Harmit S
authors.identifier: 0000-0001-6005-0016
authors.initials: HS
authors.lastname: Malik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001681:Biological Assay; D005075:Biological Evolution; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010802:Phylogeny; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D016601:RNA-Binding Proteins; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014616:Vaccinia virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C484290:IFIT1 protein, human; C092573:Ifit1 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D008780:Methyltransferases; C052744:RNA 2'-O-methyltransferase
keywords: S. cerevisiae; evolutionary biology; gene conversion; genomics; host-virus interactions; human; infectious disease; innate immunity; mRNA modification; microbiology; mouse; phylogeny; translation; virus