The human cytomegalovirus virion possesses an activated casein kinase II that allows for the rapid phosphorylation of the inhibitor of NF-kappaB, IkappaBalpha.
The human cytomegalovirus virion possesses an activated casein kinase II that allows for the rapid phosphorylation of the inhibitor of NF-kappaB, IkappaBalpha.
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人巨细胞病毒病毒体具有激活的酪蛋白激酶 II，可快速磷酸化 NF-kappaB 抑制剂 IkappaBalpha。
DOI：
10.1128/jvi.02382-06
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发表时间：
2007
影响因子：
5.4
通讯作者：
Yurochko,AndrewD
中科院分区：
文献类型：
--
作者：
Nogalski,MaciejT;Podduturi,JagatP;DeMeritt,IanB;Milford,LieslE;Yurochko,AndrewD
我们证明了人巨细胞病毒（HCMV）感染人成纤维细胞后，NF-κB信号通路被迅速诱导，并且这种诱导的NF-κB活性促进了主要立即早期启动子（MIEP）的有效反式激活。以前，我们发现主要的HCMV包膜糖蛋白gB和gH启动了NF-κB信号传导。然而，我们还假设病毒还利用其他机制快速上调NF-κB。鉴于此，我们特别假设HCMV病毒粒子含有IκBα激酶活性，允许病毒粒子进入感染细胞后IκBα直接磷酸化。对纯化的HCMV病毒体提取物进行的体外激酶测定鉴定了病毒体中真正的IκBα激酶活性。负责这种激酶活性的酶被鉴定为酪蛋白激酶II（CKII），一种细胞丝氨酸-苏氨酸蛋白激酶。CKII活性是MIEP和IE基因表达的有效反式激活所必需的。CKII通常被认为是组成型活性激酶。我们认为，这种分子特征的CKII代表了生物学原理的病毒捕获和利用这种激酶感染后早期。将CKII包装入HCMV病毒粒子中表明HCMV利用不同的分子机制快速激活NF-κB。我们认为HCMV具有多种途径来增加NF-κB活性，以确保感染后NF-κB的正确时间调节发生，并且在体内感染的不同细胞阵列（包括单核细胞和内皮细胞）中达到足够的NF-κB阈值水平。
We documented that the NF-κB signaling pathway was rapidly induced following human cytomegalovirus (HCMV) infection of human fibroblasts and that this induced NF-κB 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-κB signaling event. However, we also hypothesized that there were additional mechanisms utilized by the virus to rapidly upregulate NF-κB. In this light, we specifically hypothesized that the HCMV virion contained IκBα kinase activity, allowing for direct phosphorylation of IκBα following virion entry into infected cells. In vitro kinase assays performed on purified HCMV virion extract identified bona fide IκBα 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-κB activation. We propose that HCMV possesses multiple pathways to increase NF-κB activity to ensure that the correct temporal regulation of NF-κB occurs following infection and that sufficient threshold levels of NF-κB are reached in the diverse array of cells, including monocytes and endothelial cells, infected in vivo.