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.

DOI: http://dx.doi.org/10.7554/eLife.14228.001

eLife digest

When a virus is detected in the body, hundreds of different proteins in the immune system are rapidly produced as a first line of defense to limit the ability of the virus to multiply and spread. Many of these ‘innate’ immunity proteins have rapidly evolved in mammals in escalating molecular 'arms races' with the viruses they target. This makes it more difficult to work out exactly what job each protein performs. Even when the role of a specific protein has been determined in mice, for example, it does not always follow that the human protein with the same name will perform the same role.

The IFIT1 proteins are some of the most highly produced innate immunity proteins in mammals during viral infections. In the infected cell, host and viral proteins are both made from templates made of molecules of ribonucleic acid (RNA). Previous work showed that the IFIT1 protein in mice is able to exploit a critical chemical difference between host and virus RNA to selectively block the production of virus proteins. However, other research suggests that the human IFIT1 protein does not use the same chemical difference to distinguish between host and virus RNA.

Here, Daugherty et al. unravel the complicated evolutionary history of IFIT1 proteins to show that the mouse and human proteins are not as closely related to each other as first thought. Instead, they belong to two different protein families with distinct roles in fighting viruses. Further experiments show that the human and mouse IFIT proteins likely discriminate between host and viral RNA using different cues, leading to their action against different sets of viruses.

Daugherty et al.’s findings highlight that there are additional undiscovered chemical differences between host and viral RNA that the immune system can exploit to selectively target and stop viruses from multiplying. Furthermore, these findings re-emphasize the often-overlooked differences between the immune systems of mice and humans. The finding that mammals have such a diverse set of IFIT1 immunity proteins may directly explain why different species are susceptible to different viruses.

DOI: http://dx.doi.org/10.7554/eLife.14228.002