Control of lymphoid effector programs by the E3 ligase cullin 3

描述（由申请人提供）：宿主对病原体感染的防御严重依赖于与先天性和适应性淋巴细胞特化群体相关的效应程序的分化。每个程序都由一个签名转录因子编排，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结构域募集明确的共阻遏物复合物，以在由其锌指结合的序列特异性靶位点处诱导染色质修饰。PLZF通过微生物脂质特异性NKT细胞指导先天样效应物特性的发育获得，而Bcl-6指导T滤泡辅助细胞（TFH）和生发中心（GC）B细胞的适应性分化。这两种因子也是参与白血病和淋巴瘤的众所周知的致癌基因。基于广泛的初步研究，我们建议测试的假设，PLZF和Bcl 6招募一个新的合作伙伴，E3泛素连接酶cullin 3（Cul3），发挥关键作用，他们的转录程序，通过相关的核蛋白复合物的泛素化。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。这个项目的基本原理是，它将提供前所未有的洞察到这个主机防御程序的调节的分子细节。反过来，这些见解将允许操纵这些过程以获得治疗益处。将通过追求以下特定目标来测试所提出的假设：1）表征在其淋巴区室中缺乏Cul 3的小鼠中效应程序的失调; 2）表征Cul 3的结合和转运; 3）表征Cul 3的靶标。这些数据将被整合， 基本了解Cul3在PLZF指导的转录程序中的作用。该提案是创新的，因为它探索了一个转录因子家族的新伙伴的功能，该家族调节宿主防御病原体的重要特性。拟议的研究是重要的，因为它将提高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的特定调节成分的药物成为可能。

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.