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J. Virol. doi:10.1128/JVI.01705-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Suppression of Coronavirus Replication by Inhibition of the MEK Signaling Pathway

Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

^* To whom correspondence should be addressed. Email: zhangxuming{at}uams.edu.

	Abstract

We previously demonstrated that infection of cultured cells with murine coronavirus mouse hepatitis virus (MHV) resulted in activation of the mitogen-activated protein kinase (Raf/MEK/ERK) signal transduction pathway (Cai et al., Virology 2006, in press). Here we showed that inhibition of the Raf/MEK/ERK signaling pathway by the MEK inhibitor UO126 significantly impaired MHV progeny production (a reduction of 95-99% in virus titer), which correlated with the phosphorylation status of ERK1/2. Moreover, Knockdown of MEK1/2 and ERK1/2 by siRNAs suppressed MHV replication. The inhibitory effect of UO126 on MHV production appeared to be a general phenomenon since the effect was consistently observed in all 6 different MHV strains and in 3 different cell types tested; it was likely exerted at the post-entry steps of the virus life cycle because the virus titers were similarly inhibited from infected cells treated at 1 h prior to, during, or post infection. Furthermore, the treatment did not affect the virus entry as revealed by the virus internalization assay. Metabolic labeling and reporter gene assays demonstrated that translation of cellular and viral mRNAs appeared unaffected by UO126 treatment. However, synthesis of viral genomic and subgenomic RNAs was severely suppressed by UO126 treatment as demonstrated by a reduced incorporation of [³H]-uridine, and a decrease in chloramphenicol acetyltransferase (CAT) activity in a defective-interfering RNA-CAT reporter assay. These findings indicate that the Raf/MEK/ERK signaling pathway is involved in MHV RNA synthesis.

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