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Journal of Virology, May 2007, p. 5305-5314, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02382-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Human Cytomegalovirus Virion Possesses an Activated Casein Kinase II That Allows for the Rapid Phosphorylation of the Inhibitor of NF-{kappa}B, I{kappa}B{alpha}{triangledown}

Maciej T. Nogalski,1,# Jagat P. Podduturi,1,# Ian B. DeMeritt,1,§ Liesl E. Milford,1 and Andrew D. Yurochko1,2*

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology,1 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-39322

Received 30 October 2006/ Accepted 1 March 2007

We documented that the NF-{kappa}B signaling pathway was rapidly induced following human cytomegalovirus (HCMV) infection of human fibroblasts and that this induced NF-{kappa}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-{kappa}B signaling event. However, we also hypothesized that there were additional mechanisms utilized by the virus to rapidly upregulate NF-{kappa}B. In this light, we specifically hypothesized that the HCMV virion contained I{kappa}B{alpha} kinase activity, allowing for direct phosphorylation of I{kappa}B{alpha} following virion entry into infected cells. In vitro kinase assays performed on purified HCMV virion extract identified bona fide I{kappa}B{alpha} 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 that 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-{kappa}B activation. We propose that HCMV possesses multiple pathways to increase NF-{kappa}B activity to ensure that the correct temporal regulation of NF-{kappa}B occurs following infection and that sufficient threshold levels of NF-{kappa}B are reached in the diverse array of cells, including monocytes and endothelial cells, infected in vivo.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. Phone: (318) 675-8332. Fax: (318) 675-5764. E-mail: ayuroc{at}lsuhsc.edu

{triangledown} Published ahead of print on 7 March 2007.

# Both authors contributed equally to the work.

§ Present address: PharmAdura, LLC, 523 Route 303, Orangeburg, NY 10962.

Journal of Virology, May 2007, p. 5305-5314, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02382-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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