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.
Highlights
Mammalian antiviral defenses rely on the combined functions of a vast collection of immunity genes
Using detailed phylogenetic analyses of IFIT genes in vertebrates, made possible by deconvolving the confounding effects of recurrent gene conversion, we show that human IFIT1 and mouse IFIT1 are two distinct paralogous genes that diverged early in mammalian evolution
Using a genetic assay we developed in budding yeast, we show that mouse and other IFIT1B proteins, but not IFIT1 proteins, discriminate cap0- from cap1-mRNA methylation by selectively inhibiting growth only when a cap1-methyltransferase is missing
Summary
Mammalian antiviral defenses rely on the combined functions of a vast collection of immunity genes. One important arm of the immune system is innate, or cell intrinsic, antiviral immunity, which establishes an antiviral state in cells by signaling through the cytokine interferon (IFN) and subsequent upregulation of hundreds of genes known collectively as IFN-stimulated genes (ISGs). Among the most highly upregulated ISGs are members of the IFIT (interferon-induced with tetratricopeptide repeats) genes. Upon IFN-stimulation or viral infection, the mRNA levels of IFITs increase 100- to 1000-fold, and IFIT proteins have been implicated in inhibition of a broad range of viruses (Diamond and Farzan, 2013; Fensterl and Sen, 2015; Vladimer et al, 2014).
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