Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
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DOI：
10.1101/gad.1978310
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发表时间：
2010-12-01
影响因子：
10.5
通讯作者：
Mohr, Ian
中科院分区：
文献类型：
--
作者：
Chuluunbaatar, Uyanga;Roller, Richard;Mohr, Ian
所有病毒都需要细胞核糖体来翻译它们的mRNA。产生甲基-7（m（7））GTP加帽mRNA的病毒，如单纯疱疹病毒-1（HSV-1），通过激活mTORC 1以抑制翻译阻遏物4 E结合蛋白1（4 E-BP 1）来刺激帽依赖性翻译。在这里，我们确定HSV-1激酶Us 3伪装成Akt来激活mTORC 1。值得注意的是，Us 3与细胞激酶Akt没有序列同源性，但在与Akt相同的位点上直接磷酸化结节性硬化症复合物2（TSC 2）。TSC 2耗竭挽救了Us 3缺陷型病毒的复制，确定Us 3通过磷酸化TSC 2组成型激活mTORC 1来增强复制，有效地绕过S6 K介导的反馈抑制。此外，Us 3刺激感染细胞中Akt底物磷酸化，包括FOXO 1和GSK 3。因此，HSV-1编码具有重叠底物特异性的Akt替代物以激活mTORC 1，刺激翻译和病毒复制。这使Us 3成为一种独特的病毒激酶，具有很好的药物开发潜力。
All viruses require cellular ribosomes to translate their mRNAs. Viruses producing methyl-7 (m(7)) GTP-capped mRNAs, like Herpes Simplex Virus-1 (HSV-1), stimulate cap-dependent translation by activating mTORC1 to inhibit the translational repressor 4E-binding protein 1 (4E-BP1). Here, we establish that the HSV-1 kinase Us3 masquerades as Akt to activate mTORC1. Remarkably, Us3 displays no sequence homology with the cellular kinase Akt, yet directly phosphorylates tuberous sclerosis complex 2 (TSC2) on the same sites as Akt. TSC2 depletion rescued Us3-deficient virus replication, establishing that Us3 enhances replication by phosphorylating TSC2 to constitutively activate mTORC1, effectively bypassing S6K-mediated feedback inhibition. Moreover, Us3 stimulated Akt substrate phosphorylation in infected cells, including FOXO1 and GSK3. Thus, HSV-1 encodes an Akt surrogate with overlapping substrate specificity to activate mTORC1, stimulating translation and virus replication. This establishes Us3 as a unique viral kinase with promising drug development potential.