JVI Accepts, published online ahead of print on 7 March 2007

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J. Virol. doi:10.1128/JVI.02382-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The HCMV Virion Possesses an Activated CKII that Allows for the Rapid Phosphorylation of the Inhibitor of NF-B, IB

Maciej T. Nogalski, Jagat P. Podduturi, Ian B. DeMeritt, Liesl E. Milford, and Andrew D. Yurochko^*

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA

^* To whom correspondence should be addressed. Email: ayuroc{at}lsuhsc.edu.

We documented that the NF-B signaling pathway was rapidly induced following human cytomegalovirus (HCMV) infection of human fibroblasts and that this induced NF-B activity promoted efficient transactivation of the major immediate-early promoter (MIEP). Previously, we showed that the major HCMV envelope glycoproteins, gB and gH, initiated this NF-B signaling event. However, we also hypothesized that there were additional mechanisms utilized by the virus to rapidly upregulate NF-B. In this light, we specifically hypothesized the HCMV virion contained IB kinase activity, allowing for direct phosphorylation of IB following virion entry into infected cells. In vitro kinase assays performed on purified HCMV virion extract identified bona fide IB kinase activity in the virion. The enzyme responsible for this kinase activity was identified as casein kinase II (CKII), a cellular serine-threonine protein kinase. CKII activity was necessary for efficient transactivation of the MIEP and IE gene expression. CKII is generally considered to be a constitutively active kinase. We suggest this molecular characteristic of CKII represents the biologic rationale for the viral capture and utilization of this kinase early after infection. The packaging of CKII into the HCMV virion identifies that diverse molecular mechanisms are utilized by HCMV for rapid NF-B activation. We propose HCMV possesses multiple pathways to increase NF-B activity to insure that the correct temporal regulation of NF-B occurs following infection and that sufficient threshold levels of NF-B are reached in the diverse array of cells, including monocytes and endothelial cells, infected in vivo.

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