Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes
Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes
复制标题
DOI：
10.1128/jvi.00214-16
复制
发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Chan, Gary C.
中科院分区：
文献类型：
--
作者：
Cojohari, Olesea;Peppenelli, Megan A.;Chan, Gary C.
人巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，在免疫缺陷/幼稚宿主中引起显著的发病率和死亡率。原发性HCMV感染后，循环血液单核细胞介导病毒的全身传播。延长单核细胞短暂的48小时寿命对病毒传播过程至关重要，因为这些血液传播细胞在完全分化为巨噬细胞之前不允许病毒复制。在这里，我们表明，HCMV糖蛋白gB结合细胞表皮生长因子受体（EGFR）在HCMV进入启动快速（15分钟内）激活的凋亡抑制因子Akt，这是通过72小时维持。病毒诱导的Akt激活比正常的骨髓生长因子巨噬细胞集落刺激因子（M-CSF）更强大，并且对于感染的单核细胞绕过48小时活力检查点是必不可少的。EGFR与HCMV结合后，磷酸肌醇3-激酶（PI 3 K）的激活介导了Akt的磷酸化。此外，HCMV进入驱动开关远离PI 3 K p110 δ亚型，这是所需的未感染的单核细胞的活力，p110 β亚型，以促进感染的细胞内的Akt依赖性前生存状态。同时，与M-CSF相反，HCMV促进了含SH 2结构域的肌醇5-磷酸酶1（SHIP 1）表达的快速增加，导致通过非经典Akt活化途径的信号传导。为了确保最大的Akt活性，HCMV还诱导了负调节磷酸酶和张力蛋白同源物的早期磷酸化依赖性失活。总的来说，我们的数据表明，HCMV劫持上游Akt信号网络，诱导Akt的非传统激活，随后在48小时细胞命运检查点，HCMV的传播和持久性策略的重要一步，促生存的决定。
Human cytomegalovirus (HCMV) is a pervasive herpesvirus responsible for significant morbidity and mortality among immunodeficient/naive hosts. Following a primary HCMV infection, circulating blood monocytes mediate the systemic spread of the virus. Extending the short 48-h life span of monocytes is critical to the viral dissemination process, as these blood-borne cells are nonpermissive for virus replication until they are fully differentiated into macrophages. Here, we show that HCMV glycoprotein gB binding to cellular epidermal growth factor receptor (EGFR) during HCMV entry initiated a rapid (within 15 min) activation of the apoptosis suppressor Akt, which was maintained through 72 h. The virus-induced activation of Akt was more robust than that with the normal myeloid growth factor macrophage colony-stimulating factor (M-CSF) and was essential for infected monocytes to bypass the 48-h viability checkpoint. Activation of phosphoinositide 3-kinase (PI3K) following EGFR engagement by HCMV mediated the phosphorylation of Akt. Moreover, HCMV entry drove a switch away from the PI3K p110 delta isoform, which was required for the viability of uninfected monocytes, to the p110 beta isoform in order to facilitate the Akt-dependent prosurvival state within infected cells. Simultaneously, in contrast to M-CSF, HCMV promoted a rapid increase in SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) expression, leading to signaling through a noncanonical Akt activation pathway. To ensure maximum Akt activity, HCMV also induced an early phosphorylation-dependent inactivation of the negative regulator phosphatase and tensin homolog. Overall, our data indicate that HCMV hijacks the upstream Akt signaling network to induce a nontraditional activation of Akt and subsequently a prosurvival decision at the 48-h cell fate checkpoint, a vital step for HCMV's dissemination and persistence strategy.