Signaling functions of Peli family of E3 ubiquitin ligases

E3 泛素连接酶 Peli 家族的信号传导功能

基本信息

批准号：
9044725
负责人：
Shao-Cong Sun
金额：
$ 48.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044725
关键词：
Anti-Inflammatory Agents Anti-inflammatory Applications Grants Area Autoimmune Diseases Autoimmune Process Autoimmunity Biochemical Biological Process Cells Chronic Complex Development Disease Enzymes Event Experimental Autoimmune Encephalomyelitis Experimental Models Family Gene Targeting Genetic Goals Health IRAK1 gene Immune Immune Cell Activation Immune response Immune system Immunologic Receptors Immunosuppressive Agents Immunotherapy In Vitro Inflammation Inflammatory Interferon-beta Knockout Mice Knowledge Lead Link Lymphoid Lysine Mediating Mediator of activation protein Microglia Molecular Neuraxis Organ Pathogenesis Peripheral Phosphorylation Phosphotransferases Physiological Polyubiquitin Positioning Attribute Production Proteins Publishing Receptor Signaling Refractory Regulation Research Research Project Grants Role Signal Induction Signal Pathway Signal Transduction Specificity Symptoms System T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte TBK1 gene Therapeutic Toll-like receptors Transforming Growth Factor beta Ubiquitination Work base chemokine cytokine design experience in vivo innovation member receptor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Ubiquitination has emerged as a pivotal mechanism that regulates signal transduction in the immune system. Deregulated ubiquitination events are associated with severe immunological disorders, such as autoimmunity and chronic inflammation. A critical component of the ubiquitination system is E3 ubiquitin ligase, a superfamily (more than 600 members) of enzymes that confer specificity of ubiquitination by recognizing substrates. Since each E3 targets a small number of proteins for ubiquitination, characterization of the physiological targets of specific E3s represents a challenging and highly significant task. This information is critical for rational design of therapeutic approaches. The long-range goal of this project is to understand the immunoregulatory functions of a newly identified family of E3 ubiquitin ligases, Peli (also called Pellino). Peli proteins conjugate both lysine (K) 63- and K48-linked polyubiquitin chains, although their in vivo biological functions remains poorly understood. By gene targeting, our preliminary studies and recently published work revealed a critical, and seemingly complex, role for Peli1 in the regulation of immune receptor signaling and autoimmunity. Peli1 negatively regulates T-cell activation and maintains T-cell tolerance, and Peli1 deficiency causes systemic autoimmune symptoms. Paradoxically, the Peli1 knockout (KO) mice are refractory to the induction of experimental autoimmune encephalomyelitis (EAE), an organ-specific autoimmune disease of the central nervous system (CNS). Interestingly, although the Peli1 KO mice have hyper-production of inflammatory T cells in the peripheral lymphoid organs, these immune cells failed to migrate to the CNS. We have obtained genetic evidence that Peli1 is required for innate immune receptor signaling and induction of proinflammatory cytokines and chemokines in the CNS-resident microglial cells. These innovative findings demonstrate a pivotal and paradoxical role for Peli1 in the regulation of T-cell activation and CNS innate immune receptor signaling. Elucidation of the underlying mechanism is highly important for therapeutic approaches. Thus, the overall objective of this grant application is to understand how Peli1 exerts its immunoregulatory functions. Our hypothesis is that Peli1 targets different signaling factors for ubiquitination, thereby regulating both innate immune cell activation and T-cell tolerance. To achieve our overall objective, we will (1) examine how Peli1 regulates T-cell activation and tolerance; (2) examine how Peli1 regulates innate immune receptor signaling and CNS inflammation; and (3) elucidate the biochemical mechanisms regulating the activation and function of Peli1.

描述（由申请人提供）：泛素化已成为调节免疫系统信号转导的关键机制。放松管制的泛素化事件与严重的免疫疾病（例如自身免疫性和慢性炎症）有关。泛素化系统的一个关键成分是E3泛素连接酶，这是一种酶的超家族（超过600个成员），通过识别底物赋予泛素化的特异性。由于每个E3靶向少量的蛋白质用于泛素化，因此特定E3S的生理靶标的表征代表了一项具有挑战性且非常重要的任务。此信息对于治疗方法的合理设计至关重要。该项目的远距离目标是了解新确定的E3泛素连接酶Peli（也称为Pellino）的免疫调节功能。 peli蛋白都缀合赖氨酸（K）63-和K48连接的多泛素链，尽管它们的体内生物学功能仍然很少了解。通过基因靶向，我们的初步研究和最近发表的工作揭示了PELI1在调节免疫受体信号传导和自身免疫性中的关键且看似复杂的作用。 PELI1负调节T细胞激活并保持T细胞耐受性，而PELI1缺乏会导致全身自身免疫性症状。矛盾的是，PELI1敲除（KO）小鼠对诱导实验性自身免疫性脑脊髓炎（EAE）是一种难治性，这是一种中枢神经系统（CNS）的器官特异性自身免疫性疾病。有趣的是，尽管PELI1 KO小鼠在外周淋巴器官中炎性T细胞过多产生，但这些免疫细胞未能迁移到中枢神经系统。我们已经获得了遗传证据，表明先天免疫受体信号传导以及CNS居民小胶质细胞中促炎细胞因子和趋化因子的诱导所必需的PELI1。这些创新的发现表明，PELI1在调节T细胞激活和CNS先天免疫受体信号传导中具有关键和矛盾的作用。阐明基本机制对于治疗方法非常重要。因此，该赠款应用的总体目标是了解PELI1如何发挥其免疫调节功能。我们的假设是，PELI1靶向不同的信号传导因子以进行泛素化，从而调节先天免疫细胞活化和T细胞耐受性。为了实现我们的整体目标，我们将（1）研究PELI1如何调节T细胞激活和耐受性；（2）检查PELI1如何调节先天免疫受体信号传导和CNS炎症；（3）阐明了调节PELI1激活和功能的生化机制。