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

• 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
• 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

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中信号转导的关键机制。去调节的泛素化事件与严重的免疫紊乱相关，例如自身免疫和慢性炎症。泛素化系统的一个关键组成部分是E3泛素连接酶，它是一个超家族（超过600个成员）的酶，通过识别底物赋予泛素化的特异性。由于每个E3靶向少量的蛋白质进行泛素化，因此特定E3的生理靶标的表征代表了一项具有挑战性和高度重要的任务。这些信息对于合理设计治疗方法至关重要。该项目的长期目标是了解新鉴定的E3泛素连接酶家族Peli（也称为Pellino）的免疫调节功能。Peli蛋白结合了 赖氨酸（K）63-和K48-连接的多聚泛素链，尽管它们的体内生物学功能仍然知之甚少。通过基因靶向，我们的初步研究和最近发表的工作揭示了Peli 1在免疫受体信号传导和自身免疫调节中的关键且看似复杂的作用。Peli 1负调节T细胞活化并维持T细胞耐受性，Peli 1缺乏导致全身性自身免疫症状。特异性地，Peli 1敲除（KO）小鼠对实验性自身免疫性脑脊髓炎（EAE）的诱导是难治的，EAE是中枢神经系统（CNS）的器官特异性自身免疫性疾病。有趣的是，尽管Peli 1 KO小鼠在外周淋巴器官中过度产生炎性T细胞，但这些免疫细胞未能迁移到CNS。我们已经获得了遗传证据，表明Peli 1是先天免疫受体信号传导以及在中枢神经系统驻留的小胶质细胞中诱导促炎细胞因子和趋化因子所必需的。这些创新性的发现证明了Peli 1在调节T细胞活化和CNS先天免疫受体信号传导中的关键和矛盾作用。阐明潜在的机制对于治疗方法是非常重要的。因此，这项资助申请的总体目标是了解Peli 1如何发挥其免疫调节功能。我们的假设是Peli 1靶向不同的泛素化信号因子，从而调节 先天免疫细胞激活和T细胞耐受性。为了实现我们的总体目标，我们将（1）研究Peli 1如何调节T细胞活化和耐受性;（2）研究Peli 1如何调节先天免疫受体信号传导和CNS炎症;（3）阐明调节Peli 1活化和功能的生化机制。