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)

Abstract

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
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robertson, Professor David and Wickenhagen, Mr Arthur and Palmarini, Professor Massimo and Orton, Dr Richard and Castello, Professor Alfredo and Da Silva Filipe, Dr Ana and Busby, Joseph and Mollentze, Dr Nardus and Bamford, Dr Connor and Johnson, Dr Paul and Turnbull, Dr Matthew and Rihn, Dr Suzannah and Wilson, Professor Sam and Kuchi, Dr Srikeerthana and Shaw, Dr Andrew and Streicker, Professor Daniel and Gu, Dr Quan and Bakshi, Dr Siddharth and Stewart, Mr Douglas 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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: PLoS Biology
• Publisher: Public Library of Science
• ISSN: 1544-9173
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
168748		Identifying and characterising antiretroviral interferon stimulated genes (ISGs)	Sam Wilson	Medical Research Council (MRC)	MR/K024752/1	III - Centre for Virus Research
				Medical Research Council (MRC)	MC_UU_12014/10
				Medical Research Council (MRC)	MC_UU_12014/12
301840		Host and Viral Determinants of Interferon Resistance During HIV-1 Transmission	Sam Wilson	Medical Research Council (MRC)	MR/P022642/1	III - Centre for Virus Research
173514		Inhibition of HIV-1 by Type II Interferon	Suzannah Rihn	Wellcome Trust (WELLCOTR)	201366/Z/16/Z	III - Centre for Virus Research
307106		Epidemiology meets biotechnology: preventing viral emergence from bats	Daniel Streicker	Wellcome Trust (WELLCOTR)	217221/Z/19/Z	Institute of Biodiversity, Animal Health and Comparative Medicine