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）：严重肺炎或败血症引起的肺损伤的患者的一个临床标志是由入侵病原体触发的强大急性炎症宿主反应。在这里，在入侵病原体后激活大量的促炎细胞因子（即细胞因子风暴），激活了先天免疫系统，激活了病原体在免疫效应细胞上激活受体（T细胞，巨噬细胞等）。 TRAF的适配器分子家族是关键和高度保守的蛋白质，通过NF-KB依赖性信号传导将外表面信号（例如通过Toll受体）连接到细胞因子释放。因此，旨在选择性调节TRAF家族蛋白的可用性的操作可能会降低败血症的严重程度。然而，迄今为止，关于蛋白质稳定性水平的TRAF家族的分子调节知之甚少。在研究细菌败血症的过程中，我们发现，称为FBXO3的孤儿泛素E3连接酶亚基被激活且足以使泛素化并介导另一个相对新的泛素E3连接酶亚基的相对新的泛素降解，称为FBXL2。此外，我们发现FBXL2是抗炎药，因为它针对TRAF蛋白质的蛋白质在上皮细胞和单核细胞中处置。因此，我们的初步工作表明，通过激活FBXO3，铜绿假单胞菌会导致FBXL2泛素化和降解，从而导致免疫反应性TRAF增加，细胞因子的产生增加，并损害肺稳定性。这些数据导致了我们的新假设，即铜绿假单胞菌诱导的细胞因子释放涉及FBXO3介导的FBXL2的泛素化和降解，这又增加了促炎性的TRAF蛋白水平。我们将确定孤立的泛素E3连接酶亚基FBXO3是否与GSK3B坐标以触发FBXL2的依赖性依赖性FBXL2，从而激活TRAF蛋白以刺激细胞因子释放（AIM 1）。我们还将确定FBXO3的突变或抑制是否会减轻细菌诱导的急性肺损伤（AIM 2）。该建议提供了与细胞因子信号传导相关的新型先天免疫模型。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而奠定基础。这些研究的结果旨在作为针对FBXO3的高度选择性小分子抑制剂开发的策略的基础，以减轻细菌或败血症诱导的急性肺损伤的严重程度。