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

• 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
• 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

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 爱泼斯坦 - 巴尔病毒（EBV）是第一个确定的人类癌症病毒，与一组恶性肿瘤有关 淋巴细胞和上皮来源，是研究宿主病毒相互作用的范式。 EBV很好 已知可以操纵宿主的泛素机械以促进其潜在的持久性和肿瘤发生， 通过EBV LMP1信号转导向多个转录因子的激活（例如NFκB）检查 我们已经确定的那些包括控制免疫响应和炎症的IRF7/IRF4以及 细胞存活和生长。 LMP1信号传导的构成和平衡的激活对于生存至关重要 EBV转换的细胞及其部署或过表达导致细胞死亡。因此，描述至关重要 LMP1信号转移的详细机制，用于了解EBV介导的肿瘤发生。 p62（也称为SQSTM1，secestosoms 1）是ubiqutin传感器和一个相互作用的信号转导适配器 使用TRAF6并促进泛素信号中间体的募集，以激活NFκB 潜水员环境。反过来，p62是由NFκB活性诱导的。已知EBV LMP1在其潜伏期中激活NFκB。 但是，p62和EBV潜伏期之间的相互作用从未研究过。我们最近发表了 有趣而重要的结果，这意味着在LMP1介导的EBV潜伏期中的功能中p62。我们进一步展示 该p62在EBV延迟3中进行了更新，具体取决于LMP1/NFκB途径活动，并且p62与 LMP1和SHRNA介导的LCLS中的P62耗竭可减少细胞增殖。那我们假设EBV 潜在感染通过LMP1信号传导诱导p62表达，然后p62参与LMP1信号传导 转导导致NFκB激活。我们建议研究： 目标1。 p62的转录调节 LMP1/NFκB和LMP1/AP1途径轴； 目标2。 p62在LMP1信号转导向NFκB激活中的作用 EBV潜伏期，包括基本机制，其中包括： 一个） p62-traf6相互作用；和 b） p62作为a 泛素传感器促进信号分子的募集。这项研究的发现将确定p62是 EBV LMP1信号和长期追求的新颖和关键参与者可能会识别p62介导的功能为 EBV相关的恶性肿瘤的潜在治疗靶标。该建议涉及一系列技术 涵盖不同的生物医学学科，为学生提供了极好的培训机会 通过参与实验设计，批判性科学来建立对生物医学研究的兴趣 思考，解决问题以及科学写作和演讲。