Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus
Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus
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DOI：
10.1073/pnas.93.11.5578
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发表时间：
1996-05-28
影响因子：
11.1
通讯作者：
Sonenberg, N
中科院分区：
文献类型：
--
作者：
Gingras, AC;Svitkin, Y;Sonenberg, N
小核糖核酸病毒如脊髓灰质炎病毒和脑心肌炎病毒（EMCV）感染细胞，导致宿主蛋白质合成停止。对于脊髓灰质炎病毒，关闭的分子机制已部分阐明，但对于EMCV尚未阐明。真核生物中的翻译起始由mRNA 5'帽结构促进，多亚基翻译起始因子eIF 4F结合到mRNA 5'帽结构以促进核糖体结合。小核糖核酸病毒使用独立于帽结构的RNA翻译机制。脊髓灰质炎病毒感染引起eIF 4F的eIF 4G（以前的p220）组分的切割，并使该复合物对于帽依赖性翻译失活。相反，EMCV感染不会导致eIF 4G裂解。在这里，我们报告，EMCV和脊髓灰质炎病毒激活翻译阻遏物，4 E-BP 1，抑制帽依赖性翻译的帽结合亚基eIF 4 E结合。eIF 4 E的结合仅发生于4 E-BP 1的磷酸化不足形式，并且这种相互作用在细胞中受到高度调节。我们发现，4 E-BP 1成为去磷酸化后，EMCV和脊髓灰质炎病毒感染。在脊髓灰质炎病毒感染的细胞中，4 E-BP 1的去磷酸化在时间上与EMCV对蛋白质合成的关闭一致，但滞后于关闭和eIF 4G裂解。通过特异性抑制帽依赖性翻译而使4 E-BP 1去磷酸化可能是EMCV感染细胞中关闭现象的主要原因。
Infection of cells with picornaviruses, such as poliovirus and encephalomyocarditis virus (EMCV), causes a shutoff of host protein synthesis. The molecular mechanism of the shutoff has been partly elucidated for poliovirus but not for EMCV. Translation initiation in eukaryotes is facilitated by the mRNA 5' cap structure to which the multisubunit translation initiation factor eIF4F binds to promote ribosome binding. Picornaviruses use a mechanism for the translation of their RNA that is independent of the cap structure. Poliovirus infection engenders the cleavage of the eIF4G (formerly p220) component of eIF4F and renders this complex inactive for cap-dependent translation. In contrast, EMCV infection does not result in eIF4G cleavage. Here, we report that both EMCV and poliovirus activate a translational repressor, 4E-BP1, that inhibits cap-dependent translation by binding to the cap-binding subunit eIF4E. Binding of eIF4E occurs only to the underphosphorylated form of 4E-BP1, and this interaction is highly regulated in cells. We show that 4E-BP1 becomes dephosphorylated upon infection with both EMCV and poliovirus. Dephosphorylation of 4E-BP1 temporally coincides with the shutoff of protein synthesis by EMCV but lags behind the shutoff and eIF4G cleavage in poliovirus-infected cells. Dephosphorylation of 4E-BP1 by specifically inhibiting cap-dependent translation may be the major cause of the shutoff phenomenon in EMCV-infected cells.