Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus
Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus
复制标题
DOI：
10.1128/jvi.00559-15
复制
发表时间：
2015-09-01
影响因子：
5.4
通讯作者：
Song, Moon Jung
中科院分区：
文献类型：
--
作者：
Cheong, Woo-Chang;Park, Joo-Hee;Song, Moon Jung
在卡波西肉瘤相关疱疹病毒 (KSHV) 中，聚（ADP-核糖）聚合酶 1 (PARP-1) 充当裂解复制的抑制剂。在这里，我们证明 KSHV 在重新激活后下调 PARP-1。 KSHV 的病毒持续因子 (PF-8) 与 PARP-1 相互作用，足以以蛋白酶体依赖性方式降解 PARP-1；这种效应在鼠伽马疱疹病毒 68 中得以保留。与对照细胞相比，KSHV 感染细胞中的 PF-8 敲低导致在 PARP-1 水平增加的情况下重新激活后裂解复制减少。 PF-8 过表达降低了聚（ADP-核糖基）化（PARylated）复制和转录激活剂（RTA）的水平，并进一步增强了 RTA 介导的反式激活。这些结果表明了一种新的病毒机制，可以克服宿主因子 PARP-1 的抑制作用，从而促进伽马疱疹病毒的裂解性复制。重要性伽马疱疹病毒是重要的人类病原体，因为它们与各种肿瘤相关，并主要在宿主 B 淋巴细胞中建立潜伏期。卡波西肉瘤相关疱疹病毒（KSHV）的复制和转录激活子（RTA）是裂解性复制的中心分子开关，其表达受到许多宿主和病毒因子的严格调控。在这项研究中，我们研究了一种病毒策略来克服聚（ADP-核糖）聚合酶 1 (PARP-1) 对 RTA 活性的抑制作用。 PARP-1 是一种丰富的多功能核蛋白，在 KSHV 重新激活过程中下调。 KSHV 的病毒持续因子 (PF-8) 直接与 PARP-1 相互作用，并且足以以蛋白酶体依赖性方式降解 PARP-1 蛋白。 PF-8 降低了 PARylated RTA 的水平，并进一步促进了 RTA 介导的反式激活。由于这在另一种伽马疱疹病毒（鼠伽马疱疹病毒 68）中也是保守的，因此我们的结果表明宿主抑制因子的保守病毒调节以促进其裂解性复制。
In Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADP-ribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus.IMPORTANCEGammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication.