Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.
Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.
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DOI：
10.1371/journal.ppat.1005424
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发表时间：
2016-02
期刊：
影响因子：
6.7
通讯作者：
Ojala PM
中科院分区：
文献类型：
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作者：
Balistreri G;Viiliäinen J;Turunen M;Diaz R;Lyly L;Pekkonen P;Rantala J;Ojala K;Sarek G;Teesalu M;Denisova O;Peltonen K;Julkunen I;Varjosalo M;Kainov D;Kallioniemi O;Laiho M;Taipale J;Hautaniemi S;Ojala PM
卡波西肉瘤疱疹病毒（KSHV）导致卡波西肉瘤和某些淋巴增生性恶性肿瘤。潜伏感染在大多数肿瘤细胞中建立，而裂解复制在一小部分细胞中重新激活，这对病毒传播和疾病进展都很重要。KSHV再活化的新型调节剂的siRNA筛选鉴定了E3泛素连接酶MDM2作为病毒再活化的负调节剂。耗尽MDM2，p53的阻遏物，有利于有效激活病毒裂解转录程序和病毒再激活。在裂解复制过程中，细胞激活p53反应，积累DNA损伤并停滞在G2期。p53靶基因p21的缺失恢复了细胞周期进程，从而损害了病毒再活化级联反应，延迟了病毒复制诱导的细胞病变效应的发生。众所周知，疱疹病毒会对不同种类的应激反应重新激活，我们的研究现在强调了应激宿主细胞中的分子事件，KSHV已经进化到利用这些事件来确保有效的病毒裂解复制。众所周知，疱疹病毒会在不同的压力下醒来并重新激活。我们的研究现在强调了KSHV已经进化到用于有效病毒裂解复制的关键分子宿主细胞事件：p53的激活和p21的上调，这减缓了细胞周期，但促进了病毒复制和病毒裂解基因的转录。TP53基因突变在KSHV相关恶性肿瘤中很少发现。因此，我们的工作现在提供了一个机制解释，为什么病毒已经进化到保留p53。
Kaposi’s sarcoma herpesvirus (KSHV) causes Kaposi’s sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication. Herpesviruses are known to wake up and reactivate in response to different kinds of stress. Our study now highlights the key molecular host cell events that KSHV has evolved to utilize for efficient viral lytic replication: the activation of p53 and upregulation of p21, which slows down the cell cycle, but promotes viral replication and transcription of viral lytic genes. Mutations in TP53 gene are rarely found in KSHV-associated malignancies. Therefore, our work now provides a mechanistic explanation as to why the virus has evolved to retain p53.