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The Ubiquitin Sensor p62 Is A Novel Component of EBV LMP1 Signalosome

泛素传感器 p62 是 EBV LMP1 信号体的新型成分

基本信息

批准号：
10202127
负责人：
Ling Wang
金额：
$ 43.94万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202127
关键词：
AIDS related cancer AIDS-Related Lymphoma Adaptor Signaling Protein Autophagocytosis Binding Biological Assay Biomedical Research CRISPR/Cas technology Cell Culture Techniques Cell Death Cell Nucleus Cell Proliferation Cell Survival Cells Cellular biology Chromosomes Clinical Cytoplasm DNA Damage DNA Repair Data Discipline Epithelial Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm Equilibrium Experimental Designs Future GTF2H1 gene Gene Expression Regulation Genes Goals Hematopoietic Neoplasms Human Human Herpesvirus 4 IRF4 gene Immune response Immunoprecipitation Inflammation Intervention LMP1 Latent virus infection phase Link Lymphocyte Malignant Neoplasms Mediating Molecular Biology Oncogenic Oxidative Stress Pathway interactions Problem Solving Proteins Publishing Regulation Reporter Resources Role Series Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Students TRAF6 gene Techniques Testing Therapeutic Intervention Thinking Training Transcription Factor AP-1 Transcriptional Regulation Ubiquitin Ubiquitination Up-Regulation Viral Virus Writing cancer type carcinogenesis cell growth cell transformation clinically relevant inhibition of autophagy inhibitor/antagonist innovation insight interest knock-down knockout gene novel overexpression pathogen promoter recruit response sensor small hairpin RNA student training therapeutic target training opportunity transcription factor transforming virus translational approach tumorigenesis undergraduate student virus host interaction

项目摘要

Project Summary Epstein-Barr Virus (EBV), the first identified human cancer virus, is associated with a panel of malignancies of lymphocytic and epithelial origin, and serves as a paradigm for the study of host-virus interaction. EBV is well known to manipulate the host ubiquitin machinery to facilitate its latent persistence and oncogenesis, examplified by EBV LMP1 signal transduction to the activation of multiple transcription factors, such as NFκB and those we have identified including IRF7/IRF4, which control immune response and inflammation, as well as cell survival and growth. Constitutive and well balanced activation of LMP1 signaling is crucial for survival of EBV-transformed cells, and its depletion or overexpression leads to cell death. It is therefore vital to delineate the detailed mechanisms underlying LMP1 signal transduction for understanding EBV-mediated oncogenesis. p62 (also called SQSTM1, Sequestosome 1) is a ubiqutin sensor and a signal transducing adaptor that interacts with TRAF6 and facilitates the recruitment of ubiquitinated signal intermediators for the activation of NFκB in diverse contexts. In turn, p62 is induced by NFκB activity. EBV LMP1 is known to activate NFκB in its latency. However, the interaction between p62 and EBV latency has never been studied. We have recently published interesting and important results, which imply p62 in LMP1-mediated functions in EBV latency. We further show that p62 is upregulated in EBV latency 3, depending on LMP1/NFκB pathway activity, and that p62 interacts with LMP1 and shRNA-mediated p62 depletion in LCLs reduces cell proliferation. Thus, we hypothsize that EBV latent infection induces p62 expression through LMP1 signaling, and in turn, p62 participates in LMP1 signal transduction leading to NFκB activation. We propose to study: Aim 1. The transcriptional regulation of p62 by the LMP1/NFκB and LMP1/AP1 pathway axes; Aim 2. The role of p62 in LMP1 signaling to NFκB activation in EBV latency, including the underlying mechanisms, which include: a) p62-TRAF6 interaction; and b) p62 as a ubiquitin sensor that facilitates the recruitment of signal molecules. Findings from this study will identify p62 as a novel and critical player in EBV LMP1 signaling, and long-term pursuits may identify p62-mediated functions as a potential therapeutic target for EBV-associated malignancies. This proposal involves a series of techniques spanning different biomedical disciplines, which provide an excellent training opportunity for students to establish their interests in biomedical research by being involved in experimental design, critical scientific thinking, problem solving, and scientific writing and presentation.

项目摘要 EB病毒（EBV）是第一个被鉴定的人类癌症病毒，与一组恶性肿瘤相关，淋巴细胞和上皮起源，并作为研究宿主-病毒相互作用的范例。EBV很好已知操纵宿主泛素机制以促进其潜伏持久性和肿瘤发生，例如EBV LMP 1信号转导激活多种转录因子，如NFκB 我们已经确定的包括IRF 7/IRF 4，它们控制免疫反应和炎症，细胞存活和生长。LMP 1信号传导的组成性和良好平衡的激活对于LMP 1细胞的存活至关重要。 EBV转化的细胞，其耗竭或过度表达导致细胞死亡。因此，至关重要的是， LMP 1信号转导的详细机制，以了解EB病毒介导的肿瘤发生。 p62（也称为SQSTM 1，Sequestosome 1）是一种泛素传感器和信号转导适配器，与TRAF 6结合，并促进泛素化信号中间体的募集，以激活NFκB，不同的背景。反过来，p62被NFκB活性诱导。已知EBV LMP 1在其潜伏期激活NFκB。然而，p62和EBV潜伏期之间的相互作用从未被研究过。我们最近出版了有趣和重要的结果，这意味着p62在EBV潜伏期的LMP 1介导的功能。进一步的研究表明 p62在EBV潜伏期3中上调，依赖于LMP 1/NFκB通路活性，并且p62与LMP 1/NFκ B相互作用。 LCL中LMP 1和shRNA介导的p62缺失降低了细胞增殖。因此，我们假设EBV 潜伏感染通过LMP 1信号传导诱导p62表达，反过来，p62参与LMP 1信号传导转导导致NFκB活化。我们建议研究：目标1. p62的转录调控 LMP 1/NFκB和LMP 1/AP 1通路轴; 目标2. p62在LMP 1介导NFκB活化中的作用 EBV潜伏期，包括潜在机制，包括： a）、 p62-TRAF 6相互作用;和 B） p62作为泛素传感器，促进信号分子的募集。这项研究的结果将确定p62是一种 p62是EBV LMP 1信号传导中的一个新的和关键的参与者，长期的研究可能会将p62介导的功能鉴定为 EBV相关恶性肿瘤的潜在治疗靶点。这个建议涉及一系列的技术跨越不同的生物医学学科，为学生提供了一个极好的培训机会，通过参与实验设计，关键科学研究，思考，解决问题，科学写作和演示。