Mitogen and stress activated kinases act co-operatively with CREB during the induction of human cytomegalovirus immediate-early gene expression from latency.
Mitogen and stress activated kinases act co-operatively with CREB during the induction of human cytomegalovirus immediate-early gene expression from latency.
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DOI：
10.1371/journal.ppat.1004195
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发表时间：
2014-06
期刊：
影响因子：
6.7
通讯作者：
Reeves MB
中科院分区：
文献类型：
--
作者：
Kew VG;Yuan J;Meier J;Reeves MB
与人巨细胞病毒（HCMV）感染和再激活相关的破坏性临床后果强调了了解树突状细胞（DC）中HCMV再激活触发因素的重要性。在这里，我们表明，ERK介导的再激活依赖于促分裂原和应激激活激酶（MSK）家族。此外，这种MSK介导的应答依赖于CREB与病毒主要立即早期启动子（MIEP）的结合。具体而言，CREB与MIEP的结合为MSK募集提供了靶标。重要的是，MSK介导的组蛋白H3磷酸化是促进组蛋白去甲基化和随后HCMV从潜伏期退出所必需的。总之，这些数据表明，CREB结合MIEP是必要的招聘激酶活性的MSK启动染色质重塑MIEP所需的再活化。因此，CREB在HCMV再活化过程中的重要性是促进有利于病毒基因表达的染色质修饰以及作为经典的转录因子。显然，特异性抑制CREB和MSK之间的这种相互作用可以提供治疗干预的策略。人巨细胞病毒（HCMV）感染的免疫功能低下的个人是一个重要的原因发病。在许多情况下，疾病是由宿主预先存在的静止感染（潜伏期）的重新激活引起的，在缺乏控制性免疫应答的情况下，这是疾病的主要来源。了解从潜伏性感染到活动性（再活化）感染的转变的工作集中在控制主要病毒基因产物IE72和IE86的启动子的调节上-这是HCMV再活化的重要第一步。在这项研究中，我们相关的细胞信号通路的激活与下游激活该启动子。具体地，以ERK-MAPK依赖性方式激活细胞激酶，其显示对与关键病毒启动子结合的蛋白质的亲和力，驱动染色质结构的变化，其允许病毒基因表达-将病毒从潜伏状态释放。
The devastating clinical consequences associated with human cytomegalovirus (HCMV) infection and reactivation underscores the importance of understanding triggers of HCMV reactivation in dendritic cells (DC). Here we show that ERK-mediated reactivation is dependent on the mitogen and stress activated kinase (MSK) family. Furthermore, this MSK mediated response is dependent on CREB binding to the viral major immediate early promoter (MIEP). Specifically, CREB binding to the MIEP provides the target for MSK recruitment. Importantly, MSK mediated phosphorylation of histone H3 is required to promote histone de-methylation and the subsequent exit of HCMV from latency. Taken together, these data suggest that CREB binding to the MIEP is necessary for the recruitment of the kinase activity of MSKs to initiate the chromatin remodelling at the MIEP required for reactivation. Thus the importance of CREB during HCMV reactivation is to promote chromatin modifications conducive for viral gene expression as well as acting as a classical transcription factor. Clearly, specific inhibition of this interaction between CREB and MSKs could provide a strategy for therapeutic intervention. Human cytomegalovirus (HCMV) infection of immune-compromised individuals is a significant cause of morbidity. In a number of settings disease is caused by the reactivation of a pre-existing quiescent infection of the host (latency) which, in the absence of a controlling immune response, is a major source of disease. Work to understand the switch from a latent to active (reactivated) infection has focussed on the regulation of the promoter that controls the major viral gene products IE72 and IE86 – an important first step towards HCMV reactivation. In this study we have correlated the activation of cellular signalling pathways with the downstream activation of this promoter. Specifically, the activation of cellular kinase in an ERK-MAPK dependent manner which displays an affinity for a protein bound to a key viral promoter drives a change in the chromatin architecture that allows viral gene expression – releasing the virus from the latent state.
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DOI：
10.1073/pnas.95.7.3937
发表时间：
1998-03-31
影响因子：
11.1
作者：
Hahn, G;Jores, R;Mocarski, ES
通讯作者：
Mocarski, ES
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P
影响因子：
6.2
作者：
Hummel, Mary;Kurian, Sunil M.;Abecassis, Michael
通讯作者：
Abecassis, Michael
影响因子：
5.4
作者：
Keller, MJ;Wheeler, DG;Meier, JL
通讯作者：
Meier, JL
影响因子：
4.8
作者：
Cox, ME;Deeble, PD;Parsons, SJ
通讯作者：
Parsons, SJ