Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 replication and transcription activator regulates viral and cellular genes via interferon-stimulated response elements
Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 replication and transcription activator regulates viral and cellular genes via interferon-stimulated response elements
复制标题
DOI：
10.1128/jvi.79.9.5640-5652.2005
复制
发表时间：
2005-05-01
影响因子：
5.4
通讯作者：
Zhang, LW
中科院分区：
文献类型：
--
作者：
Zhang, J;Wang, JZ;Zhang, LW
卡波西肉瘤相关疱疹病毒（也称为人类疱疹病毒 8 [HHV-8]）复制和转录激活子 (RTA) 显然对于从病毒潜伏期到裂解复制的转变是必要且充分的。 RTA 可以通过启动子区域中的干扰素刺激反应元件 (ISRE) 样序列 (K14 ISRE) 调节开放阅读框 (ORF) K14（病毒 OX-2 同源物）和 ORF74（病毒 G 蛋白偶联受体同源物）基因。 RTA 强烈激活包含 K14 ISRE 的 K14-ORF74 启动子报告构建体和包含 K14 ISRE 的异源启动子报告构建体。 RTA 可以与 K14 ISRE 和其他 ISRE 结合，激活干扰素模拟基因 (ISG) 的启动子报告基因构建体，并选择性诱导原代内皮细胞中的三种内源 ISG：ISG-54、粘病毒抗性蛋白 1 (MxA) 和 50 kDa 的刺激反式作用因子。此外，RTA DNA 结合域中的一个区域已被鉴定为与干扰素调节因子 (IRF) 家族的 DNA 结合域具有一定的序列相似性。该区域内一个保守氨基酸的突变降低了 RTA 与 ISRE 以及其他 RTA 响应元件结合的能力。此外，该突变体未能激活 RTA 响应启动子并诱导病毒裂解基因表达。 IRF-7 中相同保守氨基酸残基的突变大大降低了其与 DNA 结合和激活 β 干扰素启动子的能力。 RTA 和 IRF 之间的序列和功能相似性表明 HHV-8 RTA 可能篡夺细胞 IRF 途径。
Kaposi's sarcoma-associated herpesvirus (also called human herpesvirus 8 [HHV-8]) replication and transcription activator (RTA) is apparently necessary and sufficient for the switch from viral latency to lytic replication. RTA may regulate open reading frame (ORF) K14 (viral OX-2 homologue) and ORF74 (viral G-protein-coupled receptor homologue) genes through an interferon-stimulated response element (ISRE)-like sequence (K14 ISRE) in the promoter region. RTA strongly activated a K14 ISRE-containing K14-ORF74 promoter reporter construct and a heterologous promoter reporter construct containing K14 ISRE. RTA could bind to K14 ISRE and other ISREs, activate promoter reporter constructs from interferon-simulated genes (ISGs), and selectively induce three endogenous ISGs in primary endothelial cells: ISG-54, myxovirus resistance protein 1 (MxA), and stimulated trans-acting factor of 50 kDa. In addition, a region in the RTA DNA-binding domain has been identified with certain sequence similarity to the DNA-binding domains of the interferon regulatory factor (IRF) family. Mutation in one conserved amino acid within this region reduced the ability of RTA to bind to ISRE as well as other RTA response elements. Furthermore, the mutant failed to activate RTA-responsive promoters and to induce viral lytic gene expression. The mutation at the same conserved amino acid residue in IRF-7 drastically reduced its ability to bind to DNA and to activate the beta interferon promoter. The sequence and functional similarities between RTA and IRFs suggest that the HHV-8 RTA may usurp the cellular IRF pathway.