Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2640-5. doi: 10.1073/pnas.0914856107. Epub 2010 Jan 22.
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.
4EBP1 可被 mTORC1 激酶磷酸化。当 mTORC1 活性受到抑制时，低磷酸化的 4EBP1 结合并隔离 eIF4E，后者是 mRNA 帽结合复合物的一个组成部分，并阻止翻译。因此，mTORC1 活性对于维持有效的翻译是必需的。人巨细胞病毒 pUL38 蛋白可保持 mTORC1 的活性，使感染细胞中的大部分 4EBP1 处于高磷酸化、无活性状态。在这里，我们报告第二个病毒蛋白 pUL69 也通过单独的机制拮抗 4EBP1 的活性。pUL69 与 eIF4A1（帽结合复合物的一个组成部分）和 poly(A)-结合蛋白直接相互作用，后者与复合物结合。当感染野生型病毒时，pUL69 积累，4EBP1 被排除在复合物之外。然而，在用 pUL69 缺失病毒感染后，4EBP1 存在于帽结合复合物中，此时几种晚期病毒编码蛋白的积累减少。我们提出，pUL69 通过将低磷酸化的 4EBP1 排除在帽结合复合物之外，支持人巨细胞病毒感染细胞中的翻译。
