Regulation of Innate Immunity by F-Box Proteins

F-Box 蛋白对先天免疫的调节

• 批准号: 8413924
• 负责人: Beibei Chen
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413924
• 关键词: Acute; Acute Lung Injury; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacterial Infections; Behavior; Clinical; Cytokine Signaling; Data; Development; Disease; Effector Cell; Epithelium; F-Box Proteins; Family; Foundations; Glycogen Synthase Kinases; Hydroxychloroquine; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Invaded; Link; Lung; Mediating; Modeling; Molecular; Molecular Models; Mus; Mutation; NF-kappa B; Natural Immunity; Organ failure; Orphan; Patients; Phase III Clinical Trials; Pneumonia; Process; Production; Protein Family; Proteins; Pseudomonas aeruginosa; Pulmonary Edema; Regulation; Role; Sepsis; Severities; Shock; Signal Transduction; Surface; System; T-Lymphocyte; TNF Receptor-Associated Factors; TNF receptor-associated factor 1; Therapeutic Intervention; Transcriptional Activation; Ubiquitination; Work; base; cytokine; design; improved; inhibitor/antagonist; link protein; lung injury; macrophage; molecular modeling; monocyte; mortality; mutant; novel; novel strategies; pathogen; protein degradation; public health relevance; receptor; response; small molecule; toll-like receptor 4; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): One clinical hallmark of patients with severe pneumonia or sepsis-induced lung injury is a robust acute inflammatory host response triggered by the invading pathogens. Here, the innate immunity system is activated to secrete large amounts of pro-inflammatory cytokines (i.e. a cytokine storm) after invading pathogens activate receptors on immune effector cells (T-cells, macrophages, etc.). The TRAF family of adaptors molecules are pivotal and highly conserved proteins that link external surface signals (e.g. via Toll receptors) to cytokine release via NF-kB dependent signaling. Thus, maneuvers designed to selectively modulate the availability of TRAF family proteins might lessen the severity of sepsis. However, to date, very little is known regarding the molecular regulation of the TRAF family at the level of protein stability. In the process of studying bacterial sepsis, we discovere that an orphan ubiquitin E3 ligase subunit, termed FBXO3, is activated and sufficient to ubiquitinate and mediate proteasomal degradation of another relatively new ubiquitin E3 ligase subunit, termed FBXL2. Further, we discovered that FBXL2 is anti-inflammatory as it targets the TRAF family of proteins for their disposal in epithelia and monocytes. Thus, our preliminary work demonstrates that P. aeruginosa, via activation of FBXO3, results in FBXL2 ubiquitination and degradation resulting in increased immunoreactive TRAFs, increased cytokine production, and impaired lung stability. These data led to our novel hypothesis that P. aeruginosa induced cytokine release involves FBXO3 mediated ubiquitination and degradation of FBXL2, which in turn increases levels of TRAF proteins which are pro-inflammatory. We will determine if an orphan ubiquitin E3 ligase subunit, FBXO3, coordinates with GSK3b to trigger ubiquitination dependent degradation of FBXL2, which in turn activates TRAF proteins to stimulate cytokine release (Aim 1). We will also determine if mutation or inhibition of FBXO3 will attenuate bacterial-induced acute lung injury (Aim 2). This proposal provides a new model of innate immunity as it relates to cytokine signaling. Execution of these studies will lay the foundation fo a significant mechanistic advance regarding the molecular regulation of the innate immune response during severe bacterial infection. Results from these studies are intended to serve as the basis for strategies directed at the development of highly selective novel small molecule inhibitors of FBXO3 to lessen the severity of bacterial or sepsis-induced acute lung injury.

描述（由申请人提供）：患有严重肺炎或脓毒症引起的肺损伤的患者的一个临床特征是由入侵病原体引发的强烈的急性炎症宿主反应。在这里，入侵的病原体激活免疫效应细胞（T细胞、巨噬细胞等）上的受体后，先天免疫系统被激活，分泌大量促炎细胞因子（即细胞因子风暴）。 TRAF 接头分子家族是关键且高度保守的蛋白质，可通过 NF-kB 依赖性信号传导将外表面信号（例如通过 Toll 受体）与细胞因子释放联系起来。因此，旨在选择性调节 TRAF 家族蛋白可用性的操作可能会减轻脓毒症的严重程度。然而，迄今为止，人们对 TRAF 家族在蛋白质稳定性水平上的分子调控知之甚少。在研究细菌性脓毒症的过程中，我们发现一个名为 FBXO3 的孤儿泛素 E3 连接酶亚基被激活，足以泛素化并介导另一个相对较新的泛素 E3 连接酶亚基 FBXL2 的蛋白酶体降解。此外，我们发现 FBXL2 具有抗炎作用，因为它针对 TRAF 蛋白家族在上皮和单核细胞中的处理。因此，我们的初步工作表明，铜绿假单胞菌通过激活 FBXO3，导致 FBXL2 泛素化和降解，从而导致免疫反应性 TRAF 增加、细胞因子产生增加和肺稳定性受损。这些数据得出了我们的新假设，即铜绿假单胞菌诱导的细胞因子释放涉及 FBXO3 介导的泛素化和 FBXL2 的降解，这反过来又增加了促炎性 TRAF 蛋白的水平。我们将确定孤儿泛素 E3 连接酶亚基 FBXO3 是否与 GSK3b 协同触发 FBXL2 的泛素化依赖性降解，进而激活 TRAF 蛋白以刺激细胞因子释放（目标 1）。我们还将确定 FBXO3 的突变或抑制是否会减轻细菌引起的急性肺损伤（目标 2）。该提议提供了一种与细胞因子信号传导相关的先天免疫的新模型。这些研究的执行将为严重细菌感染期间先天免疫反应的分子调节的重大机制进展奠定基础。这些研究的结果旨在作为开发高选择性新型 FBXO3 小分子抑制剂的策略的基础，以减轻细菌或脓毒症引起的急性肺损伤的严重程度。