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

基本信息

批准号：
8096817
负责人：
Yoshihiro Izumiya
金额：
$ 30.88万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/8096817
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 Lymphoma 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 antigen binding base body cavity cell transformation chromatin immunoprecipitation chromatin modification chromatin protein chromatin remodeling effusion infectious disease treatment innovation insight latency-associated nuclear antigen latent gene expression mutant novel paracrine protein K public health relevance reactivation from latency transcription factor tumorigenic ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The research in this R01 grant application on KSHV will produce a new understanding of regulation of gene expression and epigenetic control. Our research will provide fundamental knowledge regarding the mechanisms of viral reactivation and could produce innovative approaches for the treatment of infectious disease, especially cancer caused by this tumorigenic virus.

描述（由申请人提供）：基因表达的表观遗传调节在真核生物的许多基本生物过程中起着至关重要的作用。我们专注于定义表观遗传机制，涉及染色质蛋白的翻译后修饰，在Kaposi的肉瘤疱疹病毒（KSHV）的生命周期中，该病毒是Kaposi的Sarcoma（KS）的病因，这是AIDS与艾滋病相关的恶性。该病毒在感染细胞中表现出潜在的阶段，其中仅表达了几个病毒基因。细胞信号通路可以通过调节近100个病毒基因表达的时间级联反应活细胞以产生病毒。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非常有吸引力的模型，这是调节真核细胞转录的关键过程。小型泛素样修饰剂（SUMO）是一种蛋白质，通过共价附着（即Sumoylation）调节各种靶蛋白。 Sumoylation与磷酸化一样，用作翻译后信号分子，以将信号传输到包含相互作用基序的下游靶标（SIM）；这些靶标包括影响通常沉默转录的染色质结构的蛋白质。我们最近的研究表明，主要的病毒转录反式激活剂K-RTA是一种靶向相靶的泛素（UB）连接酶，它降解了共和性蛋白质。我们假设这种靶向相关的UB连接酶功能对于K-RTA来启动KSHV复制的裂解（生产性）相很重要，这是通过破坏潜在感染细胞中病毒偶发的抑制性环境来启动KSHV复制的。这种抑制性环境是由病毒潜伏期相关的核抗原（LANA）建立的，该抗原是一种相结合的蛋白质，将病毒发作性呈现到宿主细胞染色体的异型区域，从而维持病毒的潜在状态。该提案将检验以下假设：Sumo修饰的调节在KSHV生命周期中起着关键作用在建立该病毒的潜伏期和通过调节病毒染色质的结构来重新激活中。在第一个目标中，我们将研究K-RTA作为SUMO依赖性的泛素连接酶在KSHV复制中的作用。在第二个目标中，将分析K-RTA以相关方式起作用并影响病毒染色质的表观遗传学特征的潜在机制。综上所述，这些研究将定义K-RTA以及LANA在KSHV复制中的新作用，并将提供有关转化后修饰和染色质重塑的见解，以控制潜伏期和重新激活。公共卫生相关性：在KSHV上的R01赠款申请中的研究将对对基因表达和表观遗传控制的调节有了新的了解。我们的研究将提供有关病毒重新激活机制的基本知识，并可能为治疗传染病，尤其是由于这种肿瘤病毒引起的癌症而产生创新的方法。