Gelgor Anastasia, Gam Ze Letova Chen, Yegorov Yana, Kalt Inna, Sarid Ronit
The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar Ilan University, Ramat-Gan, Israel.
Oncotarget. 2018 Feb 15;9(17):13822-13833. doi: 10.18632/oncotarget.24497. eCollection 2018 Mar 2.
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.
卡波西肉瘤相关疱疹病毒（KSHV）是一种人类致瘤病毒，具有潜伏和裂解两种感染形式。潜伏感染是不完全的，使病毒能够建立终身感染，而裂解感染是有生产性的，对于病毒在宿主内和宿主间的传播是必需的。潜伏感染可能重新激活并转向裂解周期。这种转变是维持长期感染以及KSHV相关肿瘤发生发展的关键步骤。在本研究中，我们研究了核仁应激对KSHV裂解再激活的影响，核仁应激表现为核糖体生物合成或功能失败，且常与p53激活相关。为此，我们用放线菌素D、CX - 5461或BMH - 21处理诱导核仁应激。单独用这些化合物处理不会诱导裂解周期。然而，当与病毒蛋白K - Rta的表达相结合时，这些化合物对裂解周期的增强作用很明显。进一步使用Nutlin - 3联合处理、p53敲低以及同基因p53+/+和p53 -/-细胞的实验表明，核仁应激对裂解再激活的增强作用不依赖于p53。因此，我们的研究确定核仁应激是KSHV感染的一种新型调节因子，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会影响KSHV感染的结果。
