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

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

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Biological Assay
  • Biological Evolution
  • Carrier Proteins / genetics*
  • Carrier Proteins / immunology
  • Gene Expression Regulation
  • Host-Pathogen Interactions*
  • Humans
  • Immunity, Innate
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Mice
  • Phylogeny
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • RNA, Messenger / genetics*
  • RNA, Messenger / immunology
  • RNA-Binding Proteins
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Species Specificity
  • Vaccinia virus / genetics
  • Vaccinia virus / growth & development
  • Vaccinia virus / immunology
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • IFIT1 protein, human
  • Ifit1 protein, mouse
  • Protein Isoforms
  • RNA, Messenger
  • RNA-Binding Proteins
  • Viral Proteins
  • Methyltransferases
  • RNA 2'-O-methyltransferase