Transcriptional Control of Human Cytomegalovirus Latency

人类巨细胞病毒潜伏期的转录控制

基本信息

批准号：
10370328
负责人：
ROBERT F KALEJTA
金额：
$ 36.98万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-11 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370328
关键词：
Acquired Immunodeficiency Syndrome Affect Amino Acid Motifs Antiviral Agents Brain Glioblastoma Brain Neoplasms CREB1 gene Cardiovascular Diseases Cell Differentiation process Cells Clinical Communicable Diseases Complex Congenital Abnormality Cytomegalovirus Data Detection Disease Early Promoters Elderly Elements Epigenetic Process Event Gene Silencing Genetic Transcription Genome Glycoproteins Golgi Apparatus Heterochromatin Histone Deacetylase Human Immune Immune mediated destruction Immunity Immunologic Surveillance Infection Institutes Length Lysine Lytic Lytic Phase Malignant Neoplasms Mediating Medical Modification Myeloid Cells Organ Transplantation Pathway interactions Persons Phase Process Production Proteins Publishing Role Signal Transduction Structure Therapeutic Effect Time Transcriptional Regulation Undifferentiated Viral Virus Work activating transcription factor fighting gene repression histone methylation novel premature prevent promoter reactivation from latency recruit success transcription factor

项目摘要

Abstract Latency permits human cytomegalovirus (HCMV) to colonize its hosts for their lifetime by avoiding immune detection and clearance. The abilities of the virus to persist latently and reactivate productively are major factors in the serious medical issues caused by HCMV infections. HCMV is latent in undifferentiated myeloid cells and reactivates when these cells differentiate. The Immediate Early 1 (IE1) protein is a transcription factor that promotes progression through the viral lytic phase. During latency the levels of lytic (productive) phase proteins such as IE1 are kept extremely low (or completely absent) because the promoter that drives its expression, the Major Immediate Early Promoter (MIEP) is transcriptionally silenced by heterochromatin. Premature triggering of the lytic cycle in undifferentiated myeloid cells by spurious production of proteins like IE1 likely results in immune destruction of the reactivating cell before HCMV can complete a productive round of replication. Keeping full length IE1 protein levels low or absent protects latently infected cells from immune surveillance and restricts reactivation events until the cell differentiates. Our lab demonstrated the cellular protein Daxx and an associated histone deacetylase (HDAC) silences the MIEP when HCMV establishes latency. Likewise, we also published that the viral UL138 protein silences IE1 transcription during latency by inhibiting the recruitment of lysine-specific demethylases (KDMs) to the MIEP that remove repressive epigenetic histone methylations to activate transcription. In Aim 1, we propose to define how UL138 prevents KDM recruitment to the MIEP and silences IE1 transcription during latency from its localization at the Golgi apparatus. Deletion of UL138 from the HCMV genome revealed that at least one more suppressor of IE1 transcription is encoded by clinical strains. Such functional redundancy in silencing the MIEP underscores the importance of this process for the worldwide success of HCMV. We have now identified this novel silencer of IE transcription. In Aim 2 we propose to determine how it represses the MIEP during latency. Knowing how the MIEP is silenced during latency should reveal mechanisms through which IE1 transcription can be controlled to either inhibit or induce reactivation from latency for therapeutic effect.

抽象的潜伏期允许人类巨细胞病毒（HCMV）通过避免避免免疫检测和清除。该病毒的能力持续存在，有效地重新激活 HCMV感染引起的严重医疗问题的主要因素。 HCMV潜在未分化当这些细胞分化时，髓样细胞并重新激活。立即1（IE1）蛋白是一种转录因子通过病毒裂解阶段促进进展。在延迟期间裂解水平（生产性的）相蛋白（例如IE1）保持极低（或完全不存在），因为驱动其表达的启动子，主要的早期启动子（MIEP）是转录沉默的通过异染色质。未分化的髓样细胞中的裂解周期过早触发。像IE1这样的蛋白质的产生可能会导致重新激活细胞的免疫破坏HCMV可以完成一轮复制。保持全长IE1蛋白水平低或不存在保护从免疫监测中延迟感染的细胞并限制重新激活事件，直到细胞区分。我们的实验室证明了细胞蛋白DAXX和相关的组蛋白脱乙酰基酶（HDAC）沉默 MIEP当HCMV建立延迟时。同样，我们还发表了病毒UL138蛋白质静音通过抑制赖氨酸特异性去甲基酶的募集，IE1转录在潜伏期期间的转录（KDM）到MIEP，去除抑制性表观遗传组蛋白甲基化以激活转录。在 AIM 1，我们建议定义UL138如何防止KDM招募到MIEP和沉默IE1 潜伏期在高尔基体设备的延迟期间的转录。从HCMV中删除UL138 基因组表明，IE1转录的至少一个抑制剂由临床菌株编码。这样的沉默MIEP的功能冗余强调了这一过程在全球范围内的重要性 HCMV的成功。现在，我们已经确定了这种新颖的IE转录消音器。在AIM 2中我们建议确定其在延迟期间如何抑制MIEP。知道在延迟期间如何沉默MIEP 应揭示可以控制IE1转录以抑制或诱导的机制从潜伏期的治疗作用中重新激活。