TY - JOUR
T1 - CMPK2 restricts Zika virus replication by inhibiting viral translation
AU - Pawlak, Joanna B.
AU - Hsu, Jack Chun Chieh
AU - Xia, Hongjie
AU - Han, Patrick
AU - Suh, Hee Won
AU - Grove, Tyler L.
AU - Morrison, Juliet
AU - Shi, Pei Yong
AU - Cresswell, Peter
AU - Laurent-Rolle, Maudry
N1 - Funding Information:
JBP was supported by National Institute of Health NRSA (T32) Immuno-hematology training program (5 T32 HL 7974-19), JCCH was supported by the Cancer Research Institute Irvington Postdoctoral Fellowship. PH was supported by Transimmune AG. TLG is supported by Searle Scholars Program. PYS was supported by awards from the Sealy & Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Summerfield Robert Foundation, and Edith and Robert Zinn. MLR was supported by National Institute of Health the KL2 Mentored Clinical Scholars Program (KL2 TR001862). This work was supported by Howard Hughes Medical Institute (HHMI) the Emerging Pathogens Initiative (EPI) Program to MLR and National Institute of Health grant, (RO1 AI059167) to PC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright: © 2023 Pawlak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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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U2 - 10.1371/journal.ppat.1011286
DO - 10.1371/journal.ppat.1011286
M3 - Article
C2 - 37075076
AN - SCOPUS:85159256621
SN - 1553-7366
VL - 19
JO - PLoS pathogens
JF - PLoS pathogens
IS - 4
M1 - e1011286
ER -