One ISG encodes the enzyme oligoadenylate synthetase, which polymerizes ATP into 2ʹ–5ʹ-linked oligomers (whereas nucleotides in nucleic acids are normally linked 3ʹ–5ʹ). These 2ʹ–5ʹ-linked oligomers activate an endoribonuclease that then degrades viral RNA. A second protein induced by IFN-α and IFN-βis a dsRNA-dependent protein kinase called PKR. This serine–threonine kinase phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), thus suppressing protein translation and contributing to the inhibition of viral replication. Mx (myxoma resistant) proteins are also induced by type I interferons. Humans and wild mice have two highly similar proteins, Mx1 and Mx2, which are GTPases belonging to the dynamin protein family, but how they interfere with viral replication is not understood. Oddly, most common laboratory strains of mice have inactivated both Mx genes, and in these mice, IFN-β cannot act to protect against influenza infection.
In the last few years, several novel ISGs have been identified and linked to antiviral functions. The IFIT (IFN-induced protein with tetratricoid repeats) family contains four human and three mouse proteins that function in restraining the translation of viral RNA into proteins. IFIT1 and IFIT2 can both suppress the translation of normal capped mRNAs by binding to subunits of the eukaryotic initiation factor 3 (eIF3) complex, which prevents eIF3 from interacting with eIF2 to form the 43S pre-initiation complex (Fig. 3.36). This action may be responsible in part for the reduction in cellular proliferation induced by type I interferons. Mice lacking IFIT1 or IFIT2 show increased susceptibility to infection by certain viruses, such as vesicular stomatitis virus.
Another function of IFIT1 is to suppress translation of viral RNA that lacks a normal host modification of the 5ʹ cap. Recall that the normal mammalian 5ʹ cap is initiated by linking a 7-methylguanosine nucleotide to the first ribose sugar of the mRNA by a 5ʹ–5ʹ triphosphate bridge, to produce a structure called cap-0. This structure is further modified by cytoplasmic methylation of the 2ʹ hydroxyl groups on the first and second ribose sugars of the RNA. Methylation of the first ribose sugar produces a structure called cap-1; methylation of the second generates cap-2. IFIT1 has a high affinity for cap-0, but much lower affinity for cap-1 and cap-2. Some viruses, such as Sindbis virus (family Togaviridae), lack 2ʹ-O-methylation, and therefore are restricted by this action of IFIT1. Many viruses, such as West Nile virus and SARS coronavirus, have acquired a 2ʹe-O-methyltransferase (MTase) that produce cap-1 or cap-2 on their viral transcripts. These viruses can thus evade restriction by IFIT1.