Respiratory Syncytial Virus Limits α Subunit of Eukaryotic Translation Initiation Factor 2 (eIFα) Phosphorylation to Maintain Translation and Viral Replication
Respiratory Syncytial Virus Limits α Subunit of Eukaryotic Translation Initiation Factor 2 (eIFα) Phosphorylation to Maintain Translation and Viral Replication
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DOI：
10.1074/jbc.m109.077321
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发表时间：
2010-07-30
影响因子：
4.8
通讯作者：
Hunninghake, Gary W.
中科院分区：
文献类型：
--
作者：
Groskreutz, Dayna J.;Babor, Ellen C.;Hunninghake, Gary W.
呼吸道合胞病毒（RSV）对发病率和死亡率的影响是显着的，因为它会导致婴儿的细支气管炎，阻塞性肺病患者的病情加重，以及免疫功能低下宿主的肺炎。RSV激活蛋白激酶R（PKR），一种与限制病毒复制相关的细胞激酶（Groskreutz，D. J.，Monick，M. M.，鲍尔斯湖美国，Yarovinsky，T. O.，听着D C.的方法，Hunninghake，G. W. 176，1733-1740）。它通过自磷酸化激活，可能是由病毒复制过程中的双链RNA中间体触发的。在大多数情况下，ph-PKR通过磷酸化作用靶向真核翻译起始因子2（eIF 2 α）蛋白的α亚基，从而抑制细胞和病毒蛋白的翻译。然而，我们发现，虽然ph-PKR在RSV感染中增加，但没有观察到显著的eIF 2 α磷酸化，也没有发生蛋白质翻译的抑制。RSV感染通过有利于磷酸酶而不是激酶活性来减弱eIF 2 α磷酸化。尽管PKR被激活，但RSV通过激酶与RSV N蛋白的结合将PKR与eIF 2 α隔离。这与PKR激活后磷酸酶PP 2A与eIF 2 α的结合增加有关。结果是eIF 2 α的磷酸化受到限制，细胞和病毒蛋白质继续翻译。
The impact of respiratory syncytial virus (RSV) on morbidity and mortality is significant in that it causes bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and pneumonia in immunocompromised hosts. RSV activates protein kinase R (PKR), a cellular kinase relevant to limiting viral replication (Groskreutz, D. J., Monick, M. M., Powers, L. S., Yarovinsky, T. O., Look, D. C., and Hunninghake, G. W. (2006) J. Immunol. 176, 1733-1740). It is activated by autophosphorylation, likely triggered by a double-stranded RNA intermediate during replication of the virus. In most instances, ph-PKR targets the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) protein via phosphorylation, leading to an inhibition of translation of cellular and viral protein. However, we found that although ph-PKR increases in RSV infection, significant eIF2 alpha phosphorylation is not observed, and inhibition of protein translation does not occur. RSV infection attenuates eIF2 alpha phosphorylation by favoring phosphatase rather than kinase activity. Although PKR is activated, RSV sequesters PKR away from eIF2 alpha by binding of the kinase to the RSV N protein. This occurs in conjunction with an increase in the association of the phosphatase, PP2A, with eIF2 alpha following PKR activation. The result is limited phosphorylation of eIF2 alpha and continued translation of cellular and viral proteins.