The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis
The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis
复制标题
DOI：
10.1128/jvi.00974-10
复制
发表时间：
2010-09-15
影响因子：
5.4
通讯作者：
Muenger, Karl
中科院分区：
文献类型：
--
作者：
Spangle, Jennifer M.;Muenger, Karl
哺乳动物雷帕霉素靶点（mTOR）激酶作为一种细胞变阻器，整合了来自多种细胞信号转导途径的信号，所述信号转导途径感测生长因子和营养可利用性以及细胞内能量状态。先前报道了人乳头瘤病毒16型（HPV 16）E6癌蛋白可通过结合和E6 AP介导的mTOR抑制剂结节性硬化症复合体2（TSC 2）的降解来激活S6蛋白激酶（S6 K）（Z. Lu、X. Hu，Y.利湖，加-地Zheng，Y.郑氏，中国科学院植物研究所所长。Zhou， H.姜氏T.宁，Z.巴桑角Zhang和Y. Ke，生物化学杂志，279：35664-35670，2004; L.郑惠南叮，Z。Lu，Y. Li，Y.潘氏T. Ning和Y. Ke，基因和细胞13：285-294，2008）。我们的结果证实了HPV 16 E6的表达通过增强mTOR的磷酸化以及激活下游信号通路S6 K和真核起始因子结合蛋白1（4 E-BP 1）而引起mTORC 1活性的增加。然而，我们在表达HPV 16 E6的细胞中没有检测到TSC 2水平的降低。然而，我们发现，在营养缺乏条件下，HPV 16 E6表达通过上游激酶PDK 1和mTORC 2引起AKT活化。我们发现，HPV 16 E6表达通过增强翻译起始复合物在5“mRNA帽处的组装和帽依赖性翻译的增加而导致蛋白质合成的增加。帽依赖性翻译的增加可能是由HPV 16 E6诱导的AKT/mTORC 1活化引起的，因为翻译起始复合物的组装和帽依赖性翻译是雷帕霉素敏感的。最后，HPV 16 E6和E7癌蛋白的共表达不影响HPV 16 E6诱导的mTORC 1激活和帽依赖性翻译。HPV 16 E6介导的mTORC 1信号转导和帽依赖性翻译的激活可能是在分化的、表达HPV癌蛋白的增殖细胞中营养供应有限的条件下促进病毒复制的机制。
The mammalian target of rapamycin (mTOR) kinase acts as a cellular rheostat that integrates signals from a variety of cellular signal transduction pathways that sense growth factor and nutrient availability as well as intracellular energy status. It was previously reported that the human papillomavirus type 16 (HPV16) E6 oncoprotein may activate the S6 protein kinase (S6K) through binding and E6AP-mediated degradation of the mTOR inhibitor tuberous sclerosis complex 2 (TSC2) (Z. Lu, X. Hu, Y. Li, L. Zheng, Y. Zhou, H. Jiang, T. Ning, Z. Basang, C. Zhang, and Y. Ke, J. Biol. Chem. 279:35664-35670, 2004; L. Zheng, H. Ding, Z. Lu, Y. Li, Y. Pan, T. Ning, and Y. Ke, Genes Cells 13:285-294, 2008). Our results confirmed that HPV16 E6 expression causes an increase in mTORC1 activity through enhanced phosphorylation of mTOR and activation of downstream signaling pathways S6K and eukaryotic initiation factor binding protein 1 (4E-BP1). However, we did not detect a decrease in TSC2 levels in HPV16 E6-expressing cells. We discovered, however, that HPV16 E6 expression causes AKT activation through the upstream kinases PDK1 and mTORC2 under conditions of nutrient deprivation. We show that HPV16 E6 expression causes an increase in protein synthesis by enhancing translation initiation complex assembly at the 5' mRNA cap and an increase in cap-dependent translation. The increase in cap-dependent translation likely results from HPV16 E6-induced AKT/mTORC1 activation, as the assembly of the translation initiation complex and cap-dependent translation are rapamycin sensitive. Lastly, coexpression of the HPV16 E6 and E7 oncoproteins does not affect HPV16 E6-induced activation of mTORC1 and cap-dependent translation. HPV16 E6-mediated activation of mTORC1 signaling and cap-dependent translation may be a mechanism to promote viral replication under conditions of limited nutrient supply in differentiated, HPV oncoprotein-expressing proliferating cells.