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

Shaw, A. E. et al. (2021) The antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting. PLoS Biology, 19(9), e3001352. (doi: 10.1371/journal.pbio.3001352) (PMID:34491982) (PMCID:PMC8423302)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Robertson, Professor David and Wickenhagen, Mr Arthur and Palmarini, Professor Massimo and Orton, Dr Richard and Castello, Dr Alfredo and Da Silva Filipe, Dr Ana and Mollentze, Dr Nardus and Turnbull, Dr Matthew and Wilson, Professor Sam and Gu, Dr Quan and Stewart, Mr Douglas and Busby, Joseph and Bamford, Dr Connor and Johnson, Dr Paul and Rihn, Dr Suzannah and Kuchi, Dr Srikeerthana and Shaw, Dr Andrew and Streicker, Dr Daniel and Bakshi, Dr Siddharth and Collados Rodriguez, Dr Milagros and Sugrue, Dr Elena and Smollett, Dr Katherine
Authors: Shaw, A. E., Rihn, S. J., Mollentze, N., Wickenhagen, A., Stewart, D. G., Orton, R. J., Kuchi, S., Bakshi, S., Rodriguez Collados, M., Turnbull, M. L., Busby, J., Gu, Q., Smollett, K., Bamford, C. G.G., Sugrue, E., Johnson, P. C.D., Filipe da Silva, A., Castello, A., Streicker, D. G., Robertson, D. L., Palmarini, M., and Wilson, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN (Online):1545-7885
Copyright Holders:Copyright © 2021 Shaw et al.
First Published:First published in PLoS Biology 19(9):e3001352
Publisher Policy:Reproduced under a Creative Commons licence
Data DOI:10.5525/gla.researchdata.1159

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168748Identifying and characterising antiretroviral interferon stimulated genes (ISGs)Sam WilsonMedical Research Council (MRC)MR/K024752/1III - Centre for Virus Research
Medical Research Council (MRC)MC_UU_12014/10
Medical Research Council (MRC)MC_UU_12014/12
301840Host and Viral Determinants of Interferon Resistance During HIV-1 TransmissionSam WilsonMedical Research Council (MRC)MR/P022642/1III - Centre for Virus Research
173514Inhibition of HIV-1 by Type II InterferonSuzannah RihnWellcome Trust (WELLCOTR)201366/Z/16/ZIII - Centre for Virus Research
307106Epidemiology meets biotechnology: preventing viral emergence from batsDaniel StreickerWellcome Trust (WELLCOTR)217221/Z/19/ZInstitute of Biodiversity, Animal Health and Comparative Medicine