病毒复制
寨卡病毒
黄病毒
病毒学
生物
登革热病毒
抗病毒药物
干扰素
病毒
抗体依赖性增强
登革热
作者
Joanna B. Pawlak,Jack Chun-Chieh Hsu,Hongjie Xia,Patrick Han,Hee‐Won Suh,Tyler L. Grove,Juliet Morrison,Pei‐Yong Shi,Peter Cresswell,Maudry Laurent-Rolle
出处
期刊:PLOS Pathogens
[Public Library of Science]
日期:2023-04-19
卷期号:19 (4): e1011286-e1011286
被引量:10
标识
DOI:10.1371/journal.ppat.1011286
摘要
Flaviviruses continue to emerge as global health threats. There are currently no Food and Drug Administration (FDA) approved antiviral treatments for flaviviral infections. Therefore, there is a pressing need to identify host and viral factors that can be targeted for effective therapeutic intervention. Type I interferon (IFN-I) production in response to microbial products is one of the host’s first line of defense against invading pathogens. Cytidine/uridine monophosphate kinase 2 (CMPK2) is a type I interferon-stimulated gene (ISG) that exerts antiviral effects. However, the molecular mechanism by which CMPK2 inhibits viral replication is unclear. Here, we report that CMPK2 expression restricts Zika virus (ZIKV) replication by specifically inhibiting viral translation and that IFN-I- induced CMPK2 contributes significantly to the overall antiviral response against ZIKV. We demonstrate that expression of CMPK2 results in a significant decrease in the replication of other pathogenic flaviviruses including dengue virus (DENV-2), Kunjin virus (KUNV) and yellow fever virus (YFV). Importantly, we determine that the N-terminal domain (NTD) of CMPK2, which lacks kinase activity, is sufficient to restrict viral translation. Thus, its kinase function is not required for CMPK2’s antiviral activity. Furthermore, we identify seven conserved cysteine residues within the NTD as critical for CMPK2 antiviral activity. Thus, these residues may form an unknown functional site in the NTD of CMPK2 contributing to its antiviral function. Finally, we show that mitochondrial localization of CMPK2 is required for its antiviral effects. Given its broad antiviral activity against flaviviruses, CMPK2 is a promising potential pan-flavivirus inhibitor.
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