KSHV Rta Promoter Specification and Viral Reactivation.
KSHV Rta Promoter Specification and Viral Reactivation.
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DOI：
10.3389/fmicb.2012.00030
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发表时间：
2012
影响因子：
5.2
通讯作者：
Lukac DM
中科院分区：
文献类型：
--
作者：
Guito J;Lukac DM
病毒是专性细胞内病原体，其生物学成功取决于病毒基因组的复制和包装以及子代病毒向新宿主的传播。疱疹病毒在生物学上的成功是由于它们能够在不产生后代病毒或杀死宿主细胞的情况下复制其基因组，这一过程称为潜伏期。潜伏期允许疱疹病毒在其动物宿主中保持数十年未被检测到，同时当宿主条件有利于产生病毒后代时，保持重新激活或切换到生产性生命周期的潜力。许多宿主和病毒分子之间的直接相互作用涉及控制疱疹病毒的再激活，这表明控制该决定的复杂生物网络。一种病毒蛋白质是必要的，足以将潜伏的卡波西肉瘤相关疱疹病毒（KSHV）转换到裂解感染周期，称为K-Rta。K-Rta是一种转录激活因子，通过直接结合DNA并与细胞蛋白质相互作用来指定启动子。在这些细胞蛋白中，K-Rta与RBP-Jk的结合对于病毒再活化是必需的。与Notch信号传导的经典模型相反，RBP-Jk不是均匀和组成性地结合到潜伏的KSHV基因组，而是通过与K-Rta的相互作用募集到DNA。RBP-Jk DNA结合的刺激需要Rta与启动子中的重复和回文“CANT DNA重复”的高亲和力结合，以及与RBP-Jk形成三元复合物。然而，虽然K-Rta表达是启动KSHV再激活所必需的，但K-Rta作为开关的作用是低效的。许多因素调节K-Rta的功能，这表明KSHV的再激活可以在Rta表达后被显著调节，并挑战疱疹病毒再激活是不可避免的概念。本文对KSHV K-Rta基因的研究进展进行了综述，以探讨K-Rta基因启动子特异性在KSHV再激活过程中的作用。
Viruses are obligate intracellular pathogens whose biological success depends upon replication and packaging of viral genomes, and transmission of progeny viruses to new hosts. The biological success of herpesviruses is enhanced by their ability to reproduce their genomes without producing progeny viruses or killing the host cells, a process called latency. Latency permits a herpesvirus to remain undetected in its animal host for decades while maintaining the potential to reactivate, or switch, to a productive life cycle when host conditions are conducive to generating viral progeny. Direct interactions between many host and viral molecules are implicated in controlling herpesviral reactivation, suggesting complex biological networks that control the decision. One viral protein that is necessary and sufficient to switch latent Kaposi’s sarcoma-associated herpesvirus (KSHV) into the lytic infection cycle is called K-Rta. K-Rta is a transcriptional activator that specifies promoters by binding DNA directly and interacting with cellular proteins. Among these cellular proteins, binding of K-Rta to RBP-Jk is essential for viral reactivation. In contrast to the canonical model for Notch signaling, RBP-Jk is not uniformly and constitutively bound to the latent KSHV genome, but rather is recruited to DNA by interactions with K-Rta. Stimulation of RBP-Jk DNA binding requires high affinity binding of Rta to repetitive and palindromic “CANT DNA repeats” in promoters, and formation of ternary complexes with RBP-Jk. However, while K-Rta expression is necessary for initiating KSHV reactivation, K-Rta’s role as the switch is inefficient. Many factors modulate K-Rta’s function, suggesting that KSHV reactivation can be significantly regulated post-Rta expression and challenging the notion that herpesviral reactivation is bistable. This review analyzes rapidly evolving research on KSHV K-Rta to consider the role of K-Rta promoter specification in regulating the progression of KSHV reactivation.