Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase.
Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase.
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Kruppel相关的盒子结构域相关蛋白-1作为Kaposi肉瘤相关的疱疹病毒的潜伏期调节剂及其通过病毒蛋白激酶的调节。
DOI：
10.1158/0008-5472.can-08-4570
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Kung HJ
中科院分区：
文献类型：
--
作者：
Chang PC;Fitzgerald LD;Van Geelen A;Izumiya Y;Ellison TJ;Wang DH;Ann DK;Luciw PA;Kung HJ
卡波西肉瘤相关疱疹病毒（KSHV）与卡波西肉瘤（一种主要的艾滋病相关恶性肿瘤）的发生有关，也与血液恶性肿瘤（包括原发性渗出性淋巴瘤和多中心Castleman病）有关。像其他疱疹病毒一样，KSHV能够潜伏和裂解复制。了解与这种从潜伏到裂解复制的转变相关的分子细节是控制病毒传播的关键，并可能影响干预策略的制定。在这里，我们报告说，KAP-1/TIF 1 β，一种细胞转录抑制因子，控制染色体重塑，参与转换病毒潜伏期裂解复制的过程。通过siRNA敲低KAP-1导致KSHV再活化，其由关键转录调节因子K-Rta介导。在潜伏KSHV的细胞中，KAP-1与大多数病毒裂解基因启动子相关。K-Rta过表达诱导病毒裂解周期，伴随着KAP-1与病毒启动子结合的减少。KAP-1与异染色质的结合受到sumoylation和phoshorylation的调节。在KSHV的裂解复制过程中，KAP-1在Ser 824处被磷酸化。有几条证据直接将病毒蛋白激酶（vPK）与这种翻译后修饰联系起来。另外的研究表明，KAP-1的这种磷酸化导致其类小泛素化减少，从而降低了KAP-1在病毒启动子上浓缩染色质的能力。总之，细胞转录抑制因子KAP-1在调节KSHV潜伏期中起作用，并且vPK调节该抑制因子的染色质重塑功能。
Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can impact the development of intervention strategies. Here, we report that KAP-1/TIF1β, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by siRNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phoshorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser824. Several lines of evidence directly linked the viral protein kinase (vPK) to this post-translational modification. Additional studies demonstrated that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and vPK modulates the chromatin remodeling function of this repressor.