Svitkin Y V, Gradi A, Imataka H, Morino S, Sonenberg N
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6.
J Virol. 1999 Apr;73(4):3467-72. doi: 10.1128/JVI.73.4.3467-3472.1999.
For many members of the Picornaviridae family, infection of cells results in a shutoff of host protein synthesis. For rhinoviruses and enteroviruses, the shutoff has been explained in part by the cleavage of eukaryotic initiation factor 4GI (eIF4GI), a component of the cap-binding protein complex eIF4F. The cleavage of eIF4GI is mediated by the virus-specific proteinase 2Apro and results in inhibition of cap-dependent, but not cap-independent, translation. The inhibition of host protein synthesis after infection with human rhinovirus 14 (HRV-14) lags behind the cleavage of eIF4GI. Recently, we discovered a functional homolog of eIF4GI, termed eIF4GII, and showed that cleavage of eIF4GII coincides with the shutoff of host cell protein synthesis after poliovirus infection (Gradi et al., Proc. Natl. Acad. Sci. USA 95:11089-11094, 1998). We wished to determine whether eIF4GII cleavage kinetics could also explain the lack of correlation between the kinetics of eIF4GI cleavage and the shutoff of host protein synthesis after rhinovirus infection. In this study, we examined the correlation between human rhinovirus-induced shutoff of host protein synthesis and cleavage of eIF4GI and eIF4GII. In HRV-14-infected HeLa cells, almost no intact eIF4GI could be detected by 4 h postinfection, while only 4% of eIF4GII was cleaved at this time. By 6 h, however, 67% of eIF4GII was cleaved, and this cleavage coincided with a significant (60%) decline of host translation. These results suggest that cleavage of both eIF4GI and eIF4GII is required for HRV-mediated inhibition of host cell protein synthesis and that the cleavage of eIF4GII is the rate-limiting step in the shutoff of host cell protein synthesis after rhinovirus infection.
对于许多小核糖核酸病毒科的成员来说，细胞感染会导致宿主蛋白质合成的关闭。对于鼻病毒和肠道病毒，这种关闭部分是由于真核起始因子4GI（eIF4GI）的裂解，eIF4GI是帽结合蛋白复合物eIF4F的一个组成部分。eIF4GI的裂解由病毒特异性蛋白酶2Apro介导，并导致帽依赖性而非帽非依赖性翻译的抑制。感染人鼻病毒14（HRV - 14）后宿主蛋白质合成的抑制滞后于eIF4GI的裂解。最近，我们发现了一种eIF4GI的功能同源物，称为eIF4GII，并表明在脊髓灰质炎病毒感染后，eIF4GII的裂解与宿主细胞蛋白质合成的关闭同时发生（格拉迪等人，《美国国家科学院院刊》95:11089 - 11094，1998）。我们希望确定eIF4GII的裂解动力学是否也能解释鼻病毒感染后eIF4GI裂解动力学与宿主蛋白质合成关闭之间缺乏相关性的原因。在这项研究中，我们研究了人鼻病毒诱导的宿主蛋白质合成关闭与eIF4GI和eIF4GII裂解之间的相关性。在感染HRV - 14的HeLa细胞中，感染后4小时几乎检测不到完整的eIF4GI，而此时只有4%的eIF4GII被裂解。然而，到6小时时，67%的eIF4GII被裂解，这种裂解与宿主翻译显著（60%）下降同时发生。这些结果表明，HRV介导的宿主细胞蛋白质合成抑制需要eIF4GI和eIF4GII的裂解，并且eIF4GII的裂解是鼻病毒感染后宿主细胞蛋白质合成关闭中的限速步骤。
