The role of TRAF4 E3 ligase in IL-25-mediated allergic asthma

TRAF4 E3 连接酶在 IL-25 介导的过敏性哮喘中的作用

• 批准号: 9885028
• 负责人: Xiaoxia Li
• 金额: $ 40.17万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885028
• 关键词: Address; Affect; Allergens; Allergic; Allergic inflammation; Antibodies; Asthma; Basophils; Binding; Biological Markers; Cell Compartmentation; Cells; Cellular Structures; Complex; Development; Dose; Drug Targeting; Effector Cell; Eosinophilia; Epithelial Cells; Event; Exhibits; Extrinsic asthma; Family; Gene Expression; Human; IgE; Immune response; Immunity; Inflammation; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-9; Interleukins; JAK2 gene; Knowledge; Link; Lung; Lymphoid Cell; MAP Kinase Gene; Mediating; Molecular; Mus; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Polyubiquitination; Predisposition; Process; Production; Proteins; Pulmonary Inflammation; Receptor Signaling; Recombinant Interleukins; Reporting; Ring Finger Domain; Risk; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Sputum; Stat5 protein; Steroid Resistance; Steroids; Structure; Structure of parenchyma of lung; T-Lymphocyte; TNF receptor-associated factor 4; Testing; Therapeutic; Tumor Necrosis Factor Receptor; Ubiquitination; United States; Work; airway epithelium; airway inflammation; asthma model; asthmatic; asthmatic patient; base; cell type; chemokine; clinically significant; cytokine; eosinophil; guided inquiry; improved; insight; interleukin-17E; member; new therapeutic target; novel; novel therapeutics; patient subsets; persistent symptom; receptor; recruit; response; side effect; ubiquitin-protein ligase

Project Summary/Abstract: Around half of allergic asthmatics are classified as Th2-high (vs. Th2-low) endotype due to increased type 2 inflammation as compared with healthy controls. Airway type 2 inflammation, characterized by increased Th2 (type 2) cytokines (IL-4, IL-5, IL-9, IL-13), is mediated by interplays between multiple cell types of the lung, including structural cells (e.g. epithelial cells), and infiltrating cells (e.g. Th2 cells, group 2 innate lymphoid cells (ILC2s)). Although most of Th2-high asthmatics are responsive to current steroid-based therapy, a notable subgroup of patients with this endotype show steroid-resistance and require high-dose steroids to control their persistent symptoms. Therefore, there is an unmet need for developing novel steroid-sparing therapy to reduce the side effects associated with high-dose use of steroids. Interleukin (IL)-25 (also called IL-17E) has been known as an important upstream regulator of the classic Th2 response. The single-nucleotide polymorphism (SNP) of IL-25 receptor (IL-25R) subunit IL-17RB has been linked to risk of asthma, implicating that targeting IL- 25 may be of clinical significance in a subset of asthmatics. We previously identified Act1 (TRAF3IP2) as an essential adaptor molecule in IL-25 signaling and established its critical role in IL-25-mediated allergic pulmonary inflammation. Excitingly, we recently found that TNF receptor associated factor 4 (TRAF4) was a novel signaling molecule meditating Act1 recruitment to IL-25R, exerting a critical functional role for IL-25- mediated airway inflammation. The RING domain of TRAF4 protein is a structural feature that confers protein with E3 ligase activity. We and others have shown that TRAF4 is a genuine E3 ligase which induces polyubiquitination and the ubiquitination of its binding partners through its RING finger domain. We thus hypothesize that TRAF4 functions as an E3 ligase in IL-25 signaling impacting both Act1-dependent and - independent pathways in a cell-specific manner to promote type 2 allergic asthma. To test this hypothesis, we propose the following Specific Aims: 1) Investigate the intrinsic role of TRAF4 in different cell compartments in type 2 allergic asthma; 2) Delineate the molecular mechanism of TRAF4-mediated IL- 25 signaling. The proposed in-depth cellular and molecular studies on the TRAF4 E3 ligase in IL-25 signaling will provide significant insight into the events that initiate and maintain the asthmatic phenotype. Moreover, the results from our proposed studies may improve the potential to identify new drug targets and develop novel steroid-sparing drugs (e.g pathway-specific decoy peptides targeting IL-25 signaling) for treatment of asthma.

项目摘要/摘要： 由于2型，大约一半的过敏性哮喘患者分类为Th2-High（vs. Th2-low）内型 与健康对照相比，炎症。气道2型炎症，其特征是TH2增加 （2型）细胞因子（IL-4，IL-5，IL-9，IL-13）是由肺部多种细胞类型之间的相互作用介导的 包括结构细胞（例如上皮细胞）和浸润细胞（例如TH2细胞，第2组先天淋巴样细胞 （ILC2S））。尽管大多数Th2高哮喘患者都对当前基于类固醇的疗法有反应 该内型患者的亚组表现出类固醇的耐药性，需要大剂量类固醇来控制其 持续的症状。因此，未满足的需要开发新型类固醇的疗法以减少 与大剂量使用类固醇有关的副作用。白介素（IL）-25（也称为IL-17E）已经 被称为经典TH2响应的重要上游调节器。单核苷酸多态性 IL-25受体（IL-25R）亚基IL-17RB的（SNP）与哮喘的风险有关，这意味着针对IL- 在哮喘患者的一部分中，25可能具有临床意义。我们以前以前将ACT1（TRAF3IP2）确定为 IL-25信号传导中的必需适配器分子，并在IL-25介导的过敏性肺中确定了其关键作用 炎。令人兴奋的是，我们最近发现TNF受体相关因子4（TRAF4）是一种新颖 信号传导分子冥想ACT1募集到IL-25R，为IL-25-发挥关键的功能作用 介导的气道炎症。 TRAF4蛋白的环域是赋予蛋白质的结构特征 具有E3连接酶活性。我们和其他人表明，Traf4是一种真正的E3连接酶，可引起诱导 多泛素化及其结合伙伴通过其环手指域的泛素化。我们这样 假设TRAF4在IL-25信号传导中充当E3连接酶，影响ACT1依赖性和 - 独立的途径以细胞特异性方式促进2型过敏性哮喘。为了检验这一假设，我们 提出以下特定目的：1）研究TRAF4在不同细胞中的内在作用 2型过敏性哮喘中的隔室； 2）描述Traf4介导的IL-的分子机制 25信令。在IL-25信号中，提出的关于TRAF4 E3连接酶的深入细胞和分子研究 将为启动和维持哮喘表型的事件提供重大洞察力。而且， 我们提出的研究的结果可能会提高识别新药物靶标的潜力 类固醇的药物（例如靶向IL-25信号传导的途径特异性诱饵肽）用于治疗哮喘。