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）：针对病原体感染的宿主防御严重取决于与先天和适应性淋巴细胞专业人群相关的效应程序的分化。每个程序都由签名转录因子精心策划，但是基因调节的机制变化，在某些情况下，取决于相关的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结构域募集明确定义的共抑制配合物，以便在序列特异性的靶点位点诱导染色质修饰。 PLZF指导通过微生物脂质特异性NKT细胞对先天样效应的特性的发育，而BCL-6指导T卵泡助手（TFH）和生殖中心（GC）B细胞的自适应分化。这两个因素也是参与白血病和淋巴瘤的众所周知的癌基因。基于广泛的初步研究，我们建议检验以下假设：PLZF和BCL6募集了一个新型伴侣E3泛素连接酶Cullin 3（CUL3），该伴侣通过泛素化相关的核蛋白质复合物来对其转录程序发挥关键作用。该应用的目的是表征CUL3与PLZF的关联及其对相应淋巴细胞效应程序的影响。该项目的理由是，它将为该宿主国防计划的监管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进行治疗益处。提出的假设将通过追求以下特定目的来检验：1）表征在其淋巴间室中缺少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。数据将集成以开发 对CUL3在PLZF指导的转录程序中的作用的基本理解。该提案具有创新性，因为它探讨了一个转录因子家族的新型伴侣的功能，这些因素调节了宿主防御病原体的重要特性。拟议的研究之所以重要，是因为它将增强我们对基本淋巴细胞效应程序计划的理解，并产生新的概念和工具，从而可以开发针对免疫反应的特定监管成分的药物。