Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase
Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase
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DOI：
10.1128/jvi.01883-14
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发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Gromeier, Matthias
中科院分区：
文献类型：
--
作者：
Brown, Michael C.;Bryant, Jeffrey D.;Gromeier, Matthias
蛋白质合成是细胞中最消耗能量的过程，对变化的生理优先事项做出反应，例如，通过丝裂原激活蛋白激酶（MAPKs）发出的丝裂原应激诱导的适应信号。蛋白质合成机制的普遍地位是病毒发病因素，特别是对于正链RNA病毒，其中传入的病毒RNA的即时翻译形成宿主-病毒相互作用。在这项研究中，我们揭示了以ERK1/2和p38 α mapk相互作用激酶MNK1/2为中心的信号通路，以及它们在肠病毒1型内核糖体进入位点（IRESs）控制7-甲基鸟苷（m(7)G）“帽”非依赖性翻译中的作用。Raf-MEK-ERK1/2信号的激活以依赖于MNK1/2的方式诱导病毒ires介导的翻译。这种影响不是由于MNK作为真核起始因子（eIF） 4G结合伙伴或eIF4E（S209）激酶的已知功能。相反，MNK的催化活性通过负调控富含丝氨酸/精氨酸（SR）的蛋白激酶（SRPK）实现了病毒ires介导的翻译/宿主细胞毒性。我们的研究表明，SRPK活性是1型IRES能力、宿主细胞毒性和感染细胞中病毒增殖的主要决定因素。我们正在使用PVSRIPO（一种含有人鼻病毒2型（HRV2） IRES的1型减毒脊髓灰质炎病毒（PV） （Sabin）疫苗）靶向无约束肠病毒IRES在癌症中的活性。PVSRIPO在复发性胶质母细胞瘤（GBM）患者瘤内接种的I期临床试验显示出早期的希望。病毒在感染GBM细胞中的翻译能力是PVSRIPO抗肿瘤效果的核心要求。因此，了解感染宿主细胞中控制病毒帽独立翻译的机制至关重要。
Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e. g., upon mitogenor stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38 alpha MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m(7)G) "cap"-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs). Activation of Raf-MEK-ERK1/2 signals induced viral IRES-mediated translation in a manner dependent on MNK1/2. This effect was not due to MNK's known functions as eukaryotic initiation factor (eIF) 4G binding partner or eIF4E(S209) kinase. Rather, MNK catalytic activity enabled viral IRES-mediated translation/host cell cytotoxicity through negative regulation of the Ser/Arg (SR)-rich protein kinase (SRPK). Our investigations suggest that SRPK activity is a major determinant of type 1 IRES competency, host cell cytotoxicity, and viral proliferation in infected cells.IMPORTANCEWe are targeting unfettered enterovirus IRES activity in cancer with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES. A phase I clinical trial of PVSRIPO with intratumoral inoculation in patients with recurrent glioblastoma (GBM) is showing early promise. Viral translation proficiency in infected GBM cells is a core requirement for the antineoplastic efficacy of PVSRIPO. Therefore, it is critically important to understand the mechanisms controlling viral cap-independent translation in infected host cells.