The 'antiviral state' has shaped the CpG composition of the vertebrate interferome

Antiviral defenses in vertebrates can sense viral RNAs and mediate their destruction. The zinc-finger antiviral protein (ZAP) is an interferon stimulated gene (ISG) that recognizes CpGs (a cytosine base followed by a guanine) in viral RNAs and targets their degradation. While this is an effective form of antiviral defense, it presents a challenge for host cells since they must destroy viral RNAs while efficiently expressing their own defenses (in the interferon-stimulated cell). Here we show that as well as targeting invading pathogens, interferon-stimulated ZAP reduces the mRNA abundance of CpG rich host transcripts, providing a mechanistic explanation for the repression of multiple interferon-repressed genes (IRGs). Across multiple vertebrate species, IRGs tend to be relatively CpG-enriched, whereas highly upregulated ISGs tend to be strongly CpG-suppressed. Moreover, type I IFNs are amongst the most CpG-suppressed genes in the human genome. We propose that the targeting of CpG-rich mRNAs by the antiviral state has driven highly upregulated ISGs to possess a very low CpG content in order to escape self targeting, whereas multiple IRGs are posttranscriptionally suppressed due to their higher CpG content. Thus, antiviral effectors have not only selected compositional biases in viral genomes but have likely shaped the composition of the vertebrate interferome.