Activation of host translational control pathways by a viral developmental switch.
Activation of host translational control pathways by a viral developmental switch.
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通过病毒发育开关激活宿主翻译控制途径。
DOI：
10.1371/journal.ppat.1000334
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发表时间：
2009-03
期刊：
影响因子：
6.7
通讯作者：
Mohr I
中科院分区：
文献类型：
--
作者：
Arias C;Walsh D;Harbell J;Wilson AC;Mohr I
为了响应大量信号，潜伏的疱疹病毒基因组突然改变其发育程序，中止稳定的宿主细胞定植，转而进行有效的病毒复制，最终破坏细胞。为了实现快速的基因表达转变，新加帽的多聚腺苷酸化病毒 mRNA 必须参与并重新编程细胞翻译装置。虽然病毒基因组经历裂解再激活的转录反应已被充分记录，但细胞翻译控制途径在实现潜在裂解开关中的作用尚未描述。使用自然感染 KSHV 的 PEL 衍生 B 细胞作为模型，我们定义了有效的重新激活条件，并证明重新激活显着改变了蛋白质合成谱。新的多肽合成与 4E-BP1 翻译阻遏物失活、核 PABP 积累、eIF4F 组装以及 Mnk1 对帽结合蛋白 eIF4E 的磷酸化相关。值得注意的是，抑制 Mnk1 可通过转录后机制减少关键病毒反式激活因子 RTA 的积累，限制下游裂解蛋白的产生，并损害重新激活效率。因此，疱疹病毒从潜伏期重新激活会激活宿主帽依赖性翻译机制，这说明翻译调控在实施彻底改变细胞命运的新发育指令中的重要性。卡波西肉瘤相关疱疹病毒 (KSHV) 是一种重要的人类病原体，与所有疱疹病毒一样，它会在受感染宿主体内建立一种永久驻留状态，称为潜伏期。 KSHV 潜伏的主要部位是免疫系统细胞和血管内壁细胞。在免疫力较弱的个体中，由驻留病毒驱动的这些细胞的不适当生长可分别引起原发性渗出性淋巴瘤和卡波西肉瘤。这些危及生命的癌症在艾滋病毒/艾滋病患者中最常见，并已成为撒哈拉以南非洲部分地区的主要死亡来源。在适当的刺激下，疱疹病毒改变与宿主细胞的关系，并开始制造组装新的感染性病毒颗粒所需的蛋白质，这些颗粒可以释放和传播。为了实现这一目标，病毒劫持细胞内的关键过程并迫使它们产生病毒蛋白。在这项研究中，我们首次描述了 KSHV 在从潜伏期到这种专门的感染性病毒生产模式的转换过程中如何仔细操纵宿主蛋白质合成机制。我们的结果表明，尽管总体蛋白质合成减少，但宿主蛋白质制造机制的关键组成部分实际上受到刺激，可能会加速病毒蛋白质的产生。
In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate. Kaposi's sarcoma-associated herpesvirus (KSHV) is an important human pathogen and, like all herpesviruses, establishes a state of permanent residency in the infected host called latency. Major sites of KSHV latency are cells of the immune system and cells lining blood vessels. In individuals with weakened immunity, inappropriate growth of these cells driven by the resident virus can give rise to primary effusion lymphoma and Kaposi's sarcoma, respectively. These life-threatening cancers are most common in patients with HIV/AIDS and have become a major source of mortality in parts of sub-Saharan Africa. Under appropriate stimuli, herpesviruses change their relationship with the host cell and begin to manufacture proteins required to assemble new infectious virus particles that can be released and spread. To achieve this, the virus hijacks key processes within the cell and conscripts them into producing viral proteins. In this study, we describe for the first time how KSHV carefully manipulates the host protein synthesis machinery during the switch from latency to this specialized infectious virus production mode. Our results show that although overall protein synthesis is diminished, key components of the host's protein manufacturing machinery are actually stimulated, presumably to accelerate viral protein production.
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