Open AccessThe antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting
Author(s) -
Andrew Shaw,
Suzannah J. Rihn,
Nardus Mollentze,
Arthur Wickenhagen,
Douglas G. Stewart,
Richard Orton,
Kuchi Srikeerthana,
Siddharth Bakshi,
Milagros Rodriguez Collados,
Matthew L. Turnbull,
Joseph Busby,
Quan Gu,
Katherine Smollett,
Connor Bamford,
Elena Sugrue,
Paul Johnson,
Ana Filipe da Silva,
Alfredo Castelló,
Daniel G. Streicker,
David L. Robertson,
Massimo Palmarini,
Sam J. Wilson
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001352
Subject(s) - biology , effector , antiviral protein , interferon , cpg site , gene , genetics , innate immune system , microbiology and biotechnology , virology , rna , gene expression , dna methylation , immune system
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.