Nucleolar stress enhances lytic reactivation of the Kaposi's sarcoma-associated herpesvirus.
Nucleolar stress enhances lytic reactivation of the Kaposi's sarcoma-associated herpesvirus.
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DOI：
10.18632/oncotarget.24497
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发表时间：
2018-03-02
期刊：
影响因子：
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通讯作者：
Sarid R
中科院分区：
文献类型：
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作者：
Gelgor A;Gam Ze Letova C;Yegorov Y;Kalt I;Sarid R
卡波西肉瘤相关疱疹病毒（KSHV）是一种人类致瘤病毒，表现出潜伏性和溶解性两种感染形式。潜伏性感染是流产性的，允许病毒建立终身感染，而溶性感染是生产性的，并且需要病毒在宿主内和宿主之间传播。潜伏感染可能重新激活并转向溶解周期。这种转换是维持长期感染和kshv相关肿瘤发展的关键步骤。在这项研究中，我们研究了核仁应激对KSHV裂解再激活的影响，核糖体生物发生或功能的失败通常与p53激活相结合。为此，我们分别用放线菌素D、CX-5461或BMH-21诱导核仁应激。单独用这些化合物处理不诱导裂解循环。然而，当与病毒蛋白K-Rta的表达结合时，这些化合物明显增强了裂解周期。进一步的实验采用Nutlin-3，敲除p53和等基因p53+/+和p53-/-细胞的联合处理表明，核仁应激增强裂解再激活并不依赖于p53。因此，我们的研究确定了核仁应激是KSHV感染的一种新的调节因子，它与K-Rta表达协同作用以增加裂解再激活。这表明某些诱导核仁应激的治疗干预可能影响KSHV感染的结果。
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human tumorigenic virus exhibiting two forms of infection, latent and lytic. Latent infection is abortive and allows the virus to establish lifelong infection, while lytic infection is productive, and is needed for virus dissemination within the host and between hosts. Latent infection may reactivate and switch towards the lytic cycle. This switch is a critical step in the maintenance of long-term infection and for the development of KSHV-related neoplasms. In this study, we examined the effect of nucleolar stress, manifested by failure in ribosome biogenesis or function and often coupled with p53 activation, on lytic reactivation of KSHV. To this end, we induced nucleolar stress by treatment with Actinomycin D, CX-5461 or BMH-21. Treatment with these compounds alone did not induce the lytic cycle. However, enhancement of the lytic cycle by these compounds was evident when combined with expression of the viral protein K-Rta. Further experiments employing combined treatments with Nutlin-3, knock-down of p53 and isogenic p53+/+ and p53-/- cells indicated that the enhancement of lytic reactivation by nucleolar stress does not depend on p53. Thus, our study identifies nucleolar stress as a novel regulator of KSHV infection, which synergizes with K-Rta expression to increase lytic reactivation. This suggests that certain therapeutic interventions, which induce nucleolar stress, may affect the outcome of KSHV infection.