Control of lymphoid effector programs by the E3 ligase cullin 3

E3 连接酶 cullin 3 控制淋巴效应程序

• 批准号: 8651505
• 负责人: ALBERT S. BENDELAC
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651505
• 关键词: Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BTB/POZ Domain; Binding; Binding Sites; Cell Nucleus; Cells; Chromatin; Communicable Diseases; Complex; DNA Sequence; Data; Defect; Development; Disease; Family; Gene Expression Regulation; Goals; Health; Host Defense; Human; Immune; Immune response; Immunity; Infection; Knowledge; Lipids; Lymphocyte; Lymphoid; Malignant Neoplasms; Mediating; Mission; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nuclear; Nuclear Protein; Nuclear Proteins; Oncogenes; Population; Preventive; Process; Property; Proteins; Public Health; Recruitment Activity; Regulation; Research; Role; Structure of germinal center of lymph node; T cell differentiation; Testing; Therapeutic; Transcriptional Regulation; Ubiquitination; United States National Institutes of Health; Work; ZNF145 gene; Zinc Fingers; base; chromatin modification; cullin-3; human disease; improved; innovation; insight; leukemia/lymphoma; microbial; novel; novel strategies; pathogen; prevent; programs; public health relevance; small molecule; tool; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Host defense against pathogen infection is critically dependent on the differentiation of effector programs associated with specialized populations of innate and adaptive lymphocytes. Each program is orchestrated by a signature transcription factor, but the mechanisms of gene regulation vary and, in some cases, depend on complex interactions mediated by associated nuclear proteins. The BTB-ZF transcription factors PLZF and Bcl- 6 recruit a well-defined co-repressor complex through their BTB domain in order to induce chromatin modifications at sequence-specific target sites bound by their zinc fingers. PLZF directs the developmental acquisition of innate-like effector properties by microbial lipid-specific NKT cells, whereas Bcl-6 directs the adaptive differentiation of the T follicular helper (TFH) and the germinal center (GC) B cells. Both factors are also well-known oncogenes involved in leukemias and lymphomas. Based on extensive preliminary studies, we propose to test the hypothesis that PLZF and Bcl6 recruit a novel partner, the E3 ubiquitin ligase cullin 3 (Cul3), which exerts a critical role on their transcriptional program through ubiquitination of associated nuclear protein complexes. The objective of this application is to characterize the association of Cul3 with PLZF and its impact on the corresponding lymphocyte effector program. The rationale for this project is that it will provide unprecedented insights into the molecular details of regulation of this host defense program. In turn, these insights will allow manipulation of these processes for therapeutic benefit. The proposed hypothesis will be tested by pursuing the following specific aims: 1) to characterize the dysregulation of effector programs in mice lacking Cul3 in their lymphoid compartments; 2) to characterize the binding and transport of Cul3; 3) to characterize the targets of Cul3. The data will be integrated to develop a basic understanding of the role of Cul3 in the transcriptional program directed by PLZF. The proposal is innovative because it explores the function of a novel partner of a family of transcription factors that regulate vital properties of host defense against pathogens. The proposed research is significant because it will enhance our understanding of essential lymphocyte effector programs and generate new concepts and tools that will make it possible to develop agents that target specific regulatory components of immune responses.

描述（由申请人提供）：宿主对病原体感染的防御主要取决于与先天性和适应性淋巴细胞的特殊群体相关的效应程序的分化。每个程序都是由一个标志性转录因子精心策划的，但基因调控的机制各不相同，在某些情况下，取决于相关核蛋白介导的复杂相互作用。 BTB-ZF 转录因子 PLZF 和 Bcl-6 通过其 BTB 结构域招募明确的共阻遏物复合物，以便在其锌指结合的序列特异性靶位点诱导染色质修饰。 PLZF 指导微生物脂质特异性 NKT 细胞发育获得先天效应特性，而 Bcl-6 指导滤泡辅助 T (TFH) 和生发中心 (GC) B 细胞的适应性分化。这两个因子也是众所周知的与白血病和淋巴瘤有关的癌基因。基于广泛的初步研究，我们建议检验以下假设：PLZF 和 Bcl6 招募一个新的伙伴，E3 泛素连接酶 cullin 3 (Cul3)，它通过相关核蛋白复合物的泛素化对其转录程序发挥关键作用。本申请的目的是表征 Cul3 与 PLZF 的关联及其对相应淋巴细胞效应程序的影响。该项目的基本原理是它将为该宿主防御程序调控的分子细节提供前所未有的见解。反过来，这些见解将允许操纵这些过程以获得治疗益处。所提出的假设将通过追求以下具体目标进行检验：1）表征淋巴室中缺乏 Cul3 的小鼠中效应程序的失调； 2) 表征Cul3的结合和运输； 3）表征Cul3的目标。这些数据将被整合以开发 基本了解 Cul3 在 PLZF 指导的转录程序中的作用。该提案具有创新性，因为它探索了转录因子家族的新伙伴的功能，该转录因子家族调节宿主防御病原体的重要特性。拟议的研究意义重大，因为它将增强我们对基本淋巴细胞效应程序的理解，并产生新的概念和工具，使开发针对免疫反应特定调节成分的药物成为可能。