Kaposi sarcoma-associated herpes virus (KSHV) G protein-coupled receptor (vGPCR) activates the ORF50 lytic switch promoter: a potential positive feedback loop for sustained ORF50 gene expression.
Kaposi sarcoma-associated herpes virus (KSHV) G protein-coupled receptor (vGPCR) activates the ORF50 lytic switch promoter: a potential positive feedback loop for sustained ORF50 gene expression.
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DOI：
10.1016/j.virol.2009.07.002
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发表时间：
2009-09-15
期刊：
影响因子：
3.7
通讯作者：
Chandran, Bala
中科院分区：
文献类型：
--
作者：
Bottero, Virginie;Sharma-Walia, Neelam;Kerur, Nagaraj;Paul, Arun George;Sadagopan, Sathish;Cannon, Mark;Chandran, Bala
KSHV vGPCR是一种裂解周期相关蛋白，可通过多种信号通路激活多种转录因子，进而影响细胞和病毒基因的表达。虽然vGPCR在KSHV致瘤性中的作用已被很好地研究，但其与病毒生命周期相关的功能却知之甚少。RNA干扰使vGPCR值降低也导致KSHV裂解开关ORF50基因和蛋白表达降低。在BC3.14细胞中用多西环素诱导vGPCR也能产生更多的KSHV。当探索这一点时，观察到vGPCR表达对ORF50启动子的诱导。使用不同的ORF50启动子结构进一步研究vGPCR调控ORF50启动子的分子机制，发现vGPCR对ORF50启动子的诱导不涉及AP1，而依赖于Sp1和SP3转录因子。VGPCR信号转导导致Sp1和Sp3DNA结合活性增加，组蛋白脱乙酰酶(HDAC)活性降低。这些活性不依赖于百日咳毒素，不涉及Rho和Rac-GTP酶，涉及异源三聚体G蛋白亚基Gα12和GαQ。使用药物抑制剂和显性负性蛋白的研究发现，磷脂酶C、新的蛋白激酶C家族和蛋白激酶D是vGPCR启动的导致ORF50启动子激活的信号的一部分。综上所述，这项研究表明vGPCR在ORF50的持续表达中发挥了作用，这可能导致裂解周期基因的持续激活，最终导致病毒后代的成功形成。
KSHV vGPCR, a lytic cycle associated protein, induces several signaling pathways leading to the activation of various transcription factors and consequently the expression of cellular and viral genes. Though the role of vGPCR in KSHV tumorigenicity has been well studied, its function related to the viral life cycle is poorly understood. Reduction in vGPCR by RNA interference also resulted in the reduction in KSHV lytic switch ORF50 gene and protein expression. Induction of vGPCR by doxycycline in BC3.14 cells also resulted in more KSHV production. When this was explored, induction of the ORF50 promoter by vGPCR expression was observed. Further examination of the molecular mechanisms by which vGPCR regulates the ORF50 promoter, using various ORF50 promoter constructs, revealed that induction of ORF50 promoter by vGPCR did not involve AP1 but was dependent on Sp1 and Sp3 transcription factors. vGPCR signaling led to an increase in Sp1 and Sp3 DNA binding activity and a decrease in histone deacetylase (HDAC) activity. These activities were pertussis toxin independent, did not involve Rho and Rac-GTPases and involved the heterotrimeric G protein subunits Gα12 and Gαq. Studies using pharmacologic inhibitors and dominant negative proteins identified phospholipase C, the novel protein kinase C (novel PKC) family and protein kinase D (PKD) as part of the signaling initiated by vGPCR leading to ORF50 promoter activation. Taken together, this study suggests a role for vGPCR in the sustained expression of ORF50 which could lead to a continued activation of lytic cycle genes and ultimately to successful viral progeny formation.
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