Regulation of zika virus propagation by protein kinase c-related kinase 2
Seung-Hoon Lee, Hee Cho, Jae-Su Moon, Hae-Gwang Jung, Ji-Eun Lee, and Jong-Won Oh* Department of Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
Zika virus (ZIKV), which has been an almost neglected pathogen since its first isolation in Uganda in 1947, is a mosquito-borne arbovirus in the genus Flavivirus that now becomes a public health threat worldwide. Its infection causes neurological disorders such as microcephaly in newborn infants and Guillian-Barré syndrome in adults. In the absence of vaccines, there is an urgent need for effective control measures to prevent and treat ZIKV infection. Like other RNA viruses including many flaviviruses, ZIKV replication is mediated by an RNA replicase complex composed of viral nonstructural proteins including NS5 RNA-dependent RNA polymerase (RdRp) as well as as-yet-unidentified host factors. Until recently, efforts to develop antiviral agents against ZIKV were focused on direct-acting antivirals (DAAs) targeting viral NS proteins such as RdRp and protease. In the present study, we demonstrate the critical role of protein kinase C-related kinase 2 (PRK2) in ZIKV propagation. PRK2, an isoform of a family of serine-threonine kinases, is activated through Rho GTPases-mediated signaling pathways. It acts as a regulator of multiple cellular process controlling actin cytoskeletal organization, entry into mitosis and exit from cytokinesis, and apical junction formation. We found that pharmacological inhibition of PRK2 or its depletion by RNAi substantially reduced virus titers. Its proviral function was verified in PRK2 knockout cells where ZIKV replication, but not its cellular entry, was dramatically suppressed. In the absence of ZIKV specific DAAs, PRK2-targeting antivirals could be therapeutic options for the treatment of ZIKV infection.
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