期刊
JOURNAL OF VIROLOGY
卷 81, 期 10, 页码 5305-5314出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02382-06
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- NCRR NIH HHS [P20 RR018724, P20-RR018724] Funding Source: Medline
- NIAID NIH HHS [R01-AI56077, R01 AI056077] Funding Source: Medline
- NIGMS NIH HHS [P20 GM103433] Funding Source: Medline
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(x 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.
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