Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase
Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase
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DOI：
10.1128/jvi.78.20.11030-11039.2004
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发表时间：
2004-10-01
影响因子：
5.4
通讯作者：
Alwine, JC
中科院分区：
文献类型：
--
作者：
Kudchodkar, SB;Yu, YJ;Alwine, JC
由细胞激酶介导的哺乳动物雷帕霉素靶蛋白（mTOR）在正常（非应激）条件下激活帽依赖性翻译。然而，翻译被细胞应激反应或雷帕霉素治疗所抑制，从而抑制mTOR激酶的活性。我们发现，在人巨细胞病毒（HCMV）感染过程中，当mTOR激酶活性因缺氧胁迫或雷帕霉素治疗而受到抑制时，病毒蛋白的合成和病毒的产生相对正常。利用雷帕霉素抑制mTOR，我们发现HCMV感染诱导两种mTOR效应物，真核起始因子4E （eIF4E）结合蛋白（4E- bp）和eIF4G磷酸化。病毒诱导的eIF4G磷酸化不依赖于mTOR和磷脂酰肌醇3-激酶（PI3K），而4E-BP磷酸化不依赖于mTOR，但依赖于PI3K。HCMV感染不会诱导第三种mTOR效应物p70S6激酶（p70S6K）不依赖mTOR的磷酸化。我们发现hcmv诱导的eIF4G和4E-BP磷酸化与帽结合蛋白eIF4E与eIF4F翻译起始复合物中eIF4G的关联相关。因此，即使mTOR信号被抑制，HCMV诱导维持eIF4F复合物完整性的机制。
Signaling mediated by the cellular kinase mammalian target of rapamycin (mTOR) activates cap-dependent translation under normal (nonstressed) conditions. However, translation is inhibited by cellular stress responses or rapamycin treatment, which inhibit mTOR kinase activity. We show that during human cytomegalovirus (HCMV) infection, viral protein synthesis and virus production proceed relatively normally when mTOR kinase activity is inhibited due to hypoxic stress or rapamycin treatment. Using rapamycin inhibition of mTOR, we show that HCMV infection induces phosphorylation of two mTOR effectors, eucaryotic initiation factor 4E (eIF4E) binding protein (4E-BP) and eIF4G. The virally induced phosphorylation of eIF4G is both mTOR and phosphatidylinositol 3-kinase (PI3K) independent, whereas the phosphorylation of 4E-BP is mTOR independent, but PI3K dependent. HCMV infection does not induce mTOR-independent phosphorylation of a third mTOR effector, p70S6 kinase (p70S6K). We show that the HCMV-induced phosphorylation of eIF4G and 4E-BP correlates with the association of eIF4E, the cap binding protein, with eIF4G in the eIF4F translation initiation complex. Thus, HCMV induces mechanisms to maintain the integrity of the eIF4F complex even when mTOR signaling is inhibited.