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信号转导的关键机制。无调节的泛素化事件与严重的免疫紊乱有关，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，这是一个超家族（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靶向少量泛素化蛋白，表征特定E3的生理靶标是一项具有挑战性和高度意义的任务。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发现的E3泛素连接酶家族Peli（也称为Pellino）的免疫调节功能。Peli蛋白将两者结合