Aberrant regulation of the Akt signaling network by human cytomegalovirus allows for targeting of infected monocytes.
Aberrant regulation of the Akt signaling network by human cytomegalovirus allows for targeting of infected monocytes.
复制标题
DOI：
10.1016/j.antiviral.2018.07.015
复制
发表时间：
2018-10
影响因子：
7.6
通讯作者：
Chan GC
中科院分区：
文献类型：
--
作者：
Peppenelli MA;Miller MJ;Altman AM;Cojohari O;Chan GC
原发性外周血单核细胞负责原发性感染后人巨细胞病毒（HCMV）的血行播散。为了促进病毒传播，HCMV通过在病毒进入期间刺激Akt的非典型激活来延长单核细胞的自然短的48小时寿命，这导致抗凋亡蛋白的特定子集的表达增加。在这项研究中，Akt信号网络的整体分析显示，与正常的骨髓生长因子相比，HCMV诱导了整个网络更强大的激活。此外，我们发现HCMV激活的Akt和应激反应转录热休克因子1（HSF 1）之间存在独特的相互作用，允许合成含有帽和内部核糖体进入位点（IRES）的抗凋亡mRNA，如髓细胞白血病-1（Mcl-1）和X连锁凋亡抑制因子（XIAP）。由于通常在细胞应激期间发生从帽依赖性翻译到IRES介导的翻译的转换，HCMV同时驱动两种类型的翻译的能力产生受感染单核细胞的活力所需的促存活蛋白的独特环境。事实上，我们发现XIAP的抑制导致约99%的HCMV感染的单核细胞死亡，而对未感染细胞的活力具有最小的影响。总之，这些数据表明，异常激活的Akt网络的HCMV诱导的一个独特的子集的抗凋亡蛋白的受感染的单核细胞的生存所需的上调。因此，我们的研究强调了利用这些病毒诱导的变化来预防免疫功能低下患者中HCMV暴露高风险的病毒传播的可能性。
Primary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. In order to facilitate viral spread, HCMV extends the naturally short 48-hour lifespan of monocytes by stimulating a non-canonical activation of Akt during viral entry, which leads to the increased expression of a specific subset of antiapoptotic proteins. In this study, global analysis of the Akt signaling network showed HCMV induced a more robust activation of the entire network when compared to normal myeloid growth factors. Furthermore, we found a unique interplay between HCMV-activated Akt and the stress response transcription heat shock factor 1 (HSF1) that allowed for the synthesis of both cap- and internal ribosome entry site (IRES)-containing antiapoptotic mRNAs such as myeloid cell leukemia-1 (Mcl-1) and X-linked inhibitor of apoptosis (XIAP), respectively. As generally a switch from cap-dependent to IRES-mediated translation occurs during cellular stress, the ability of HCMV to concurrently drive both types of translation produces a distinct milieu of prosurvival proteins needed for the viability of infected monocytes. Indeed, we found inhibition of XIAP led to death of ~99% of HCMV-infected monocytes while having minimal effect on the viability of uninfected cells. Taken together, these data indicate that the aberrant activation of the Akt network by HCMV induces the upregulation of a unique subset of antiapoptotic proteins specifically required for the survival of infected monocytes. Consequently, our study highlights the possibility of exploiting these virus-induced changes to prevent viral spread in immunocompromised patients at high-risk for HCMV exposure.
登录
查看更多内容
影响因子：
3.7
作者：
Chou SD;Prince T;Gong J;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
3.7
作者：
Basu A;Sridharan S
通讯作者：
Sridharan S
影响因子：
56.9
作者：
Franke, TF;Kaplan, DR;Toker, A
通讯作者：
Toker, A
影响因子：
3.4
作者：
Emery, VC
通讯作者：
Emery, VC
DOI：
10.4049/jimmunol.0903025
发表时间：
2010-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chan G;Nogalski MT;Bentz GL;Smith MS;Parmater A;Yurochko AD
通讯作者：
Yurochko AD