Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1
Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1
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DOI：
10.1073/pnas.0914856107
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发表时间：
2010-02-09
影响因子：
11.1
通讯作者：
Shenk, Thomas E.
中科院分区：
文献类型：
--
作者：
Aoyagi, Mariko;Gaspar, Miguel;Shenk, Thomas E.
4EBP 1被mTORC 1激酶磷酸化。当mTORC 1活性受到抑制时，低磷酸化的4EBP 1结合并隔离eIF4 E（mRNA帽结合复合物的组分），并阻断翻译。因此，需要mTORC1活性来维持主动翻译。人巨细胞病毒pUL38蛋白保留mTORC 1活性，使感染细胞中的大部分E4BP 1处于过度磷酸化的非活性状态。在这里，我们报告说，第二个病毒蛋白，pUL69，也拮抗4EBP 1的活性，但通过一个单独的机制。pUL69直接与eIF4A1（帽结合复合物的元件）和与复合物结合的poly（A）结合蛋白相互作用。当pUL69在用野生型病毒感染期间积累时，4EBP 1从复合物中排除。然而，4EBP 1存在于感染pUL69缺陷型病毒后的帽结合复合物中，与几种晚期病毒编码蛋白的积累减少一致。我们建议，pUL69支持翻译人巨细胞病毒感染的细胞排除低磷酸化4EBP 1从帽结合复合物。
4EBP1 is phosphorylated by the mTORC1 kinase. When mTORC1 activity is inhibited, hypophosphorylated 4EBP1 binds and sequesters eIF4E, a component of the mRNA cap-binding complex, and blocks translation. As a consequence, mTORC1 activity is needed to maintain active translation. The human cytomegalovirus pUL38 protein preserves mTORC1 activity, keeping most of the E4BP1 in the infected cell in a hyperphosphorylated, inactive state. Here we report that a second viral protein, pUL69, also antagonizes the activity of 4EBP1, but by a separate mechanism. pUL69 interacts directly with eIF4A1, an element of the cap-binding complex, and the poly(A)-binding protein, which binds to the complex. When pUL69 accumulates during infection with wild-type virus, 4EBP1 is excluded from the complex. However, 4EBP1 is present in the cap-binding complex after infection with a pUL69-deficient virus, coincident with reduced accumulation of several late virus-coded proteins. We propose that pUL69 supports translation in human cytomegalovirus-infected cells by excluding hypophosphorylated 4EBP1 from the cap-binding complex.