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Elife. 2016 May 31;5. pii: e14228. doi: 10.7554/eLife.14228.

Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals.

Author information

1
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.
2
Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, United States.
3
Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States.
4
Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, United States.
5
Department of Microbiology, University of Washington School of Medicine, Seattle, United States.
6
Department of Medicine, University of Washington School of Medicine, Seattle, United States.

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.

KEYWORDS:

S. cerevisiae; evolutionary biology; gene conversion; genomics; host-virus interactions; human; infectious disease; innate immunity; mRNA modification; microbiology; mouse; phylogeny; translation; virus

PMID:
27240734
PMCID:
PMC4887208
DOI:
10.7554/eLife.14228
[Indexed for MEDLINE]
Free PMC Article

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