Transcriptional Control of Human Cytomegalovirus Latency

人类巨细胞病毒潜伏期的转录控制

• 批准号: 9894713
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-11 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894713
• 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; 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

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.

摘要 潜伏期允许人巨细胞病毒（HCMV）通过避免感染而在其宿主体内终生定植。 免疫检测和清除。该病毒潜伏存在并有效地重新激活的能力是 HCMV感染引起的严重医疗问题的主要因素。HCMV潜伏于未分化的 骨髓细胞，并在这些细胞分化时重新激活。IE1（Immediate Early 1）蛋白是一种 通过病毒裂解阶段促进进展的转录因子。在潜伏期， （生产）相蛋白如IE1保持极低（或完全不存在），因为 启动子驱动其表达，主要立即早期启动子（MIEP）转录沉默 异染色质假单胞菌对未分化髓系细胞溶解周期的过早触发 IE 1等蛋白质的产生可能会在HCMV之前导致重新激活细胞的免疫破坏 完成一轮富有成效的复制。保持全长IE1蛋白水平较低或不存在可保护 潜伏感染的细胞免受免疫监视，并限制再激活事件，直到细胞分化。 我们的实验室证明了细胞蛋白Daxx和相关的组蛋白脱乙酰酶（HDAC）沉默了细胞内的蛋白质。 HCMV建立潜伏期时的MIEP。同样，我们还发表了病毒UL138蛋白沉默 通过抑制赖氨酸特异性去甲基化酶的募集在潜伏期期间IE1转录 在一些实施方案中，MIEP与KDM（KDM）结合，其去除抑制性表观遗传组蛋白甲基化以激活转录。在 目的1，我们建议定义UL138如何阻止KDM招募到MIEP并沉默IE1 在潜伏期内从其在高尔基体的定位转录。从HCMV中删除UL138 基因组显示，至少有一个IE1转录抑制基因由临床菌株编码。等 沉默MIEP的功能冗余强调了这一过程对全世界的重要性。 HCMV的成功。我们现在已经确定了这种新的沉默IE转录。在目标2中，我们提出 来确定它在潜伏期是如何抑制MIEP的了解MIEP在延迟期间如何静默 应该揭示IE1转录可以被控制以抑制或诱导的机制， 从潜伏期重新激活以获得治疗效果。