PI3K-dependent upregulation of Mcl-1 by human cytomegalovirus is mediated by epidermal growth factor receptor and inhibits apoptosis in short-lived monocytes.
PI3K-dependent upregulation of Mcl-1 by human cytomegalovirus is mediated by epidermal growth factor receptor and inhibits apoptosis in short-lived monocytes.
复制标题
DOI：
10.4049/jimmunol.0903025
复制
发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Yurochko AD
中科院分区：
文献类型：
--
作者：
Chan G;Nogalski MT;Bentz GL;Smith MS;Parmater A;Yurochko AD
单核细胞是巨细胞病毒感染的主要靶点，也是导致病毒血源性传播的关键细胞类型。从生物学上讲，这些细胞在循环中的寿命很短，只有1-3天，但感染的细胞仍能存活数周，尽管在这段时间内缺乏病毒抗凋亡基因的表达。为了了解巨细胞病毒抑制单核细胞凋亡初始阶段的机制，我们重点研究了病毒对感染后早期有利于生存的细胞信号事件的调节。我们在这里证明，病毒上调的磷脂酰肌醇3-激酶[PI(3)K]途径促进了感染后细胞凋亡的早期阻断。时间转录组和蛋白质分析表明，Mcl-1是Bcl2家族的成员，在HCMV感染的早期阶段以PI(3)K依赖的方式瞬时诱导。与生存研究一致，病毒诱导的Mcl-1表达水平在感染后72小时消散至模拟水平。通过使用Mcl-1特异的siRNA，我们证实了Mcl-1作为单核细胞凋亡的关键早期调节因子的功能。最后，我们发现，在病毒结合过程中，HCMV的参与和表皮生长因子受体(EGFR)的激活触发了Mcl-1的上调。总体而言，我们的数据表明，在HCMV感染的早期阶段，需要通过依赖PI(3)K上调的Mcl-1激活EGFR/PI(3)K信号通路，以绕过自然短暂的单核细胞的凋亡，从而确保病毒持续策略的早期步骤。
Monocytes are a primary target for HCMV infection and are a key cell type responsible for hematogenous dissemination of the virus. Biologically these cells have a short life span of 1–3 days in the circulation, yet infected cells remain viable for weeks despite the lack of viral anti-apoptotic gene expression during this time period. To understand the mechanism by which HCMV inhibits the initial phase of monocyte apoptosis, we focused on the viral modulation of early pro-survival cell signalling events following infection. We demonstrate here that the viral upregulation of the phosphatidylinositol 3-kinase [PI(3)K] pathway promotes an early block in apoptosis following infection. Temporal transcriptome and protein analyses revealed Mcl-1, a member of the Bcl-2 family, was transiently induced in a PI(3)K-dependent manner during the early stages of HCMV infection. In accord with the survival studies, virally induced levels of Mcl-1 expression dissipated to mock levels by 72 hours post infection. Through the use of Mcl-1 specific siRNA, we confirmed the functional role that Mcl-1 plays as a key early regulator of apoptosis in monocytes. Lastly, we showed that HCMV engagement and activation of the epidermal growth factor receptor (EGFR) during viral binding triggered the upregulation of Mcl-1. Overall, our data indicates that activation of the EGFR/PI(3)K signalling pathway, via the PI(3)K-dependent upregulation of Mcl-1, is required to circumvent apoptosis in naturally short-lived monocytes during the early stages of HCMV infection, thus ensuring the early steps in the viral persistence strategy.
登录
查看更多内容
影响因子：
39.2
作者：
JORDAN, MC;ROUSSEAU, WE;NOBLE, GR
通讯作者：
NOBLE, GR
影响因子：
6
作者：
Chan, G;Hemmings, DG;Guilbert, LJ
通讯作者：
Guilbert, LJ
影响因子：
--
作者：
Liu, Hongtao;Huang, QiQuan;Pope, Richard M.
通讯作者：
Pope, Richard M.
影响因子：
5.4
作者：
Chan, Gary;Bivins-Smith, Elizabeth R.;Yurochko, Andrew D.
通讯作者：
Yurochko, Andrew D.
影响因子：
6.4
作者：
Manez, R;Kusne, S;Ehrlich, GD
通讯作者：
Ehrlich, GD