Journal Article

The antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting

Orton, Richard J., Turnbull, Matthew L., Da Silva, Ana Filipe, Castello, Alfredo, Wilson, Sam J., Smollett, Katherine, Kuchi, Srikeerthana, Busby, Joseph, Streicker, Daniel G., Johnson, Paul C. D., Palmarini, Massimo, Mollentze, Nardus, Stewart, Douglas G., Sugrue, Elena, Shaw, Andrew E., Bamford, Connor G. G., Rihn, Suzannah J., Gu, Quan, Bakshi, Siddharth, Collados, Mila Rodriguez, Robertson, David L., Wickenhagen, Arthur

2021

Overview

Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs while sparing the host mRNAs that encode antiviral effectors. Here, we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon (IFN) stimulation, the CpG-targeting antiviral effector zinc-finger antiviral protein (ZAP) reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to be relatively CpG rich. In contrast, highly upregulated ISGs tend to be strongly CpG suppressed. Thus, ZAP is an example of an effector that has not only selected compositional biases in viral genomes but also appears to have notably shaped the composition of host transcripts in the vertebrate interferome.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: A549 Cells / Accuracy / Antiviral drugs / Antiviral state / Bias / Biology and Life Sciences / Cell Line / Composition / CpG islands / Dinucleoside Phosphates / Effectors / Fibroblasts / Genes / Genomes / Humans / Interferon / Interferon Regulatory Factors - genetics / Interferon-beta - pharmacology / Methods / Nucleotides / Proteins / Research and analysis methods / RNA sequencing / RNA, Messenger / RNA, Viral / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Vertebrates / Virus Physiological Phenomena / Viruses / Zinc finger proteins