K-Rta as a Novel SUMO and Epigenetic Regulator

K-Rta 作为新型相扑和表观遗传调节剂

• 批准号: 8462230
• 负责人: Yoshihiro Izumiya
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462230
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Applications Grants; B-Cell Lymphomas; Binding; Binding Proteins; Biochemical Genetics; Biological Process; Body cavities; Cancer Etiology; Cell physiology; Cells; Chromatin; Chromatin Structure; Chromosomes; Complex; Coupled; Data; Defect; Development; Disease; Environment; Epigenetic Process; Episome; Eukaryota; Eukaryotic Cell; Exhibits; Gene Expression; Gene Expression Regulation; Genetic Transcription; HIV; Herpesviridae; Heterochromatin; Histones; Human; In Vitro; Kaposi Sarcoma; Knowledge; Life Cycle Stages; Ligase; Link; Lytic; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Modeling; Modification; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Mutate; Oncogenic; Pathway interactions; Patients; Phase; Phosphorylation; Play; Post-Translational Protein Processing; Process; Proteins; Recruitment Activity; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stream; Structure; Testing; Trans-Activators; Translations; Ubiquitin; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus; Virus Latency; abstracting; antigen binding; base; body cavity; cell transformation; chromatin immunoprecipitation; chromatin modification; chromatin protein; chromatin remodeling; infectious disease treatment; innovation; insight; latency-associated nuclear antigen; latent gene expression; mutant; novel; paracrine; primary effusion lymphoma; protein K; reactivation from latency; transcription factor; tumorigenic; ubiquitin ligase; ubiquitin-protein ligase

Abstract: Epigenetic regulation of gene expression plays a critical role in many fundamental biological processes in eukaryotes. We have focused on defining epigenetic mechanisms, involving post-translation modification of chromatin proteins, in the life cycle of Kaposi's sarcoma herpesvirus (KSHV), which is an etiological agent of Kaposi's sarcoma (KS), an AIDS-associated malignancy. This virus exhibits a latent phase in infected cells in which only a few viral genes are expressed. Cell signaling pathways can reactivate latent cells to produce virus through a temporal cascade that regulates expression of nearly 100 viral genes. Thus, KSHV is a very attractive model to study epigenetic mechanisms that affect chromatin structure and dynamics, which are key processes regulating transcription in eukaryotic cells. The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes, including heterochromatin formation, by covalent attachment (i.e., sumoylation) to a diverse array of target proteins. Sumoylation, like phosphorylation, serves as a post-translational signal molecule to transmit signals to down-stream targets containing a SUMO-interacting motif (SIM); these targets include proteins that impact chromatin structure that generally silence transcription. Our recent studies show that the main viral transcriptional transactivator, K-Rta, is a SUMO-targeting ubiquitin (Ub) ligase, which degrades SUMO- modified proteins. We hypothesize that this SUMO-targeting Ub ligase function is important for K-Rta to initiate the lytic (productive) phase of KSHV replication by disrupting the repressive environment surrounding of the viral episome in latently infected cells. This repressive environment is established by the viral latency- associated nuclear antigen (LANA), which is a SUMO-binding protein that tethers viral episomes to heterochromatic regions of host cell chromosomes and thereby maintains the latent state of the virus. This proposal will test the hypothesis that the regulation of SUMO modification plays a key role in the KSHV life cycle in both establishment of latency and reactivation of this virus by modulating the structure of viral chromatin. In the first Aim, we will investigate the role of K-Rta as a SUMO-dependent ubiquitin ligase in KSHV replication. In the second Aim, the potential mechanisms whereby K-Rta acts in a SUMO-dependent manner and affects the epigenetic signature of viral chromatin will be analyzed. Taken together, these studies will define a new role of K-Rta, as well as LANA, in KSHV replication, and will provide insights into the post- translational modifications and chromatin remodeling that govern latency and reactivation.

摘要： 基因表达的表观遗传调控在许多基础生物学中起着关键作用 真核生物中的过程。我们的重点是定义表观遗传机制，涉及翻译后 卡波西肉瘤疱疹病毒(KSHV)生活史中染色质蛋白的修饰 卡波西肉瘤(KS)的病原体，这是一种与艾滋病相关的恶性肿瘤。这种病毒呈现潜伏期。 在只表达少数病毒基因的受感染细胞中。细胞信号通路可以重新激活潜伏期 细胞通过调节近100个病毒基因的表达的时间级联来产生病毒。因此， KSHV是研究影响染色质结构和动力学的表观遗传机制的一个非常有吸引力的模型， 它们是真核细胞中调节转录的关键过程。 小泛素样修饰物(SUMO)是一种调节多种细胞过程的蛋白质， 包括异染色质形成，通过共价连接(即，总甲基化)到不同的靶阵列上 蛋白质。与磷酸化一样，相思甲基化也是翻译后信号分子，用于传递信号 下游含有相扑相互作用基序(SIM)的靶标；这些靶标包括影响 通常抑制转录的染色质结构。我们最近的研究表明，主要的病毒 转录反式激活因子K-RTA是一种相扑靶向泛素(Ub)连接酶，它能降解相扑-泛素。 修饰的蛋白质。我们推测这种相扑靶向Ub连接酶功能对K-RTA很重要 通过破坏周围的压抑环境启动KSHV复制的裂解(生产)阶段 在潜伏感染的细胞中感染病毒。这种压抑的环境是由病毒潜伏期建立的- 相关核抗原(LANA)，这是一种相扑结合蛋白，将病毒表型连接到 宿主细胞染色体的异染色区，从而维持病毒的潜伏状态。这 该提案将检验相扑修饰的调节在KSHV寿命中起关键作用的假设 通过调节病毒结构在病毒潜伏时间的建立和重新激活过程中的循环 染色质。在第一个目标中，我们将研究K-RTA作为相扑依赖的泛素连接酶在 KSHV复制。在第二个目标中，K-RTA在相扑依赖中的潜在作用机制 将分析病毒染色质的表观遗传特征的方式和影响。总而言之，这些研究 将定义K-RTA以及LANA在KSHV复制中的新角色，并将提供对后 控制潜伏期和重新激活的翻译修饰和染色质重塑。