Distinct effects of knocking down MEK1 and MEK2 on replication of herpes simplex virus type 2.
During infection, viruses hijack various host cell components and programs for their amplification, among which is the canonical ERK signaling pathway, mainly consisting of three tiered serine/threonine kinases, Raf, MEK and ERK. MEK1 and MEK2 are two isoforms of the kinase operating immediately upstream of ERK, and connecting Raf and ERK by phosphorylating ERK. Previous studies have suggested that different isoforms of MEK have distinct biological functions, although their in vitro kinase function may be redundant. However, little is known about the isoform-specific effects of these kinases on viral propagation. In this study, we showed that herpes simplex virus type 2 (HSV-2) infection of human embryonic kidney (HEK) 293 cells induced a sustained activation of ERK1/2. Inhibition of this ERK activation by U0126, a specific inhibitor of MEK1/2, severely impaired virus production. A similar reduction of virus production was also seen following transfection of cells with siRNAs for MEK1/2. Interestingly, a specific knockdown of MEK1 with siRNAs caused a marked inhibition of viral titers, viral proteins and virus-induced cytopathic effect (CPE), whereas silencing MEK2 had little effect. Therefore, our results demonstrate that MEK1 and MEK2 act differently and that HSV-2 hijacks host MEK1 for its own amplification. To our knowledge, this is the first report showing inhibition of HSV-2 replication by targeting human MEK1. This study also suggests that MEK1 could be a potential target for anti-HSV-2 therapy, which may minimize damage to the host cells engendered by targeting both MEK1 and MEK2.
Zhang
Hao
H
Department of Microbiology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, PR China.
Feng
Hai
H
Luo
Lingqi
L
Zhou
Qi
Q
Luo
Zhijun
Z
Peng
Yihong
Y
D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D018258:Herpesvirus 2, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D014779:Virus Replication
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human