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

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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.

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Most cited references 44

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The placental mammal ancestor and the post-K-Pg radiation of placentals.

Maureen A. O'Leary, Jonathan I. Bloch, John J. Flynn … (2013)

To discover interordinal relationships of living and fossil placental mammals and the time of origin of placentals relative to the Cretaceous-Paleogene (K-Pg) boundary, we scored 4541 phenomic characters de novo for 86 fossil and living species. Combining these data with molecular sequences, we obtained a phylogenetic tree that, when calibrated with fossils, shows that crown clade Placentalia and placental orders originated after the K-Pg boundary. Many nodes discovered using molecular data are upheld, but phenomic signals overturn molecular signals to show Sundatheria (Dermoptera + Scandentia) as the sister taxon of Primates, a close link between Proboscidea (elephants) and Sirenia (sea cows), and the monophyly of echolocating Chiroptera (bats). Our tree suggests that Placentalia first split into Xenarthra and Epitheria; extinct New World species are the oldest members of Afrotheria.

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IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.

Andreas Pichlmair, Caroline Lassnig, Carol-Ann Eberle … (2011)

Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5' terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.

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Conventional and unconventional mechanisms for capping viral mRNA

Etienne Decroly, François Ferron, Julien Lescar … (2011)

Key Points mRNAs are protected at their 5′ ends by a cap structure consisting of an N7-methylated GTP molecule linked to the first transcribed nucleotide by a 5′–5′ triphosphate bond. The cap structure is essential for RNA splicing, export and stability, and allows the ribosomal complex to recognize mRNAs and ensure their efficient translation. Uncapped RNA molecules are degraded in cytoplasmic granular compartments called processing bodies and may be detected as 'non-self' by the host cell, triggering antiviral innate immune responses through the production of interferons. Conventional RNA capping (that is, of mRNAs from the host cell and from DNA viruses) requires hydrolysis of the 5′ γ-phosphate of RNA by an RNA triphosphatase, transfer of a GMP molecule onto the 5′-end of RNA by a guanylyltransferase, and methylation of this guanosine by an (guanine-N7)-methyltransferase. Subsequent methylations on the first and second transcribed nucleotides by (nucleoside-2′-O)-methyltransferases form cap-1 and cap-2 structures. Viruses have evolved highly diverse capping mechanisms to acquire cap structures using their own or cellular capping machineries, or by stealing cap structures from cellular mRNAs. Virally encoded RNA-capping machineries are diverse in terms of their genetic components, protein domain organization, enzyme structures, and reaction mechanisms and pathways, making viral RNA capping an attractive target for antiviral-drug design.

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PubMed ID:: 27240734

PMC ID:: 4887208

DOI:: 10.7554/eLife.14228

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

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

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Most cited references 44

The placental mammal ancestor and the post-K-Pg radiation of placentals.

IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.

Conventional and unconventional mechanisms for capping viral mRNA

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