Characterization of IKK-phosphorylated ITCH in TNF signaling

IKK 磷酸化 ITCH 在 TNF 信号传导中的表征

基本信息

批准号：
9081233
负责人：
Jessica Marie Perez
金额：
$ 3.36万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9081233
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Affect Agonist Alleles Antibodies Antiviral Agents Applications Grants Autoimmune Diseases Bacteria Biochemical Biochemistry Cell Nucleus Cell Wall Cells Characteristics Chronic Chronic Disease Complex DNA Sequence Alteration Data Detection Disease Down-Regulation Equilibrium Etiology Evaluation Event Exhibits Eye Feedback Functional disorder Genetic Genetic Polymorphism Genetic study Granulomatous Health Hereditary Disease Homeostasis Human I Kappa B-Alpha Immune Immune response Immune system Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-17 Lead Life Light Link Lung Lymph Node Tissue Mediating Methods Modeling Modification Molecular Biology Mus Pathogenesis Pathway interactions Patients Pattern recognition receptor Peptides Peptidoglycan Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Post-Translational Protein Processing Predisposition Prevalence Production Productivity Proteins Quality of life RIPK2 gene Role Sarcoidosis Signal Pathway Signal Transduction Site Skin Staging Syndrome T-Lymphocyte TBK1 gene TNF gene TNFRSF1A gene TRAF4 gene Testing Therapeutic Tissues Training Treatment Efficacy Tumor Necrosis Factor Receptor Ubiquitination United States Virus early onset fungus gain of function gain of function mutation genome wide association study in vitro activity inhibitor/antagonist insight macrophage mouse model mutant neutrophil novel pathogen programs reconstitution research study response therapeutic biomarker therapeutic target transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Sarcoidosis is a genetic inflammatory disorder that can manifest in tissues of the lymph node, eye and skin, but most commonly manifests in lung. This chronic granulomatous disorder is still a disease of unknown etiology, but exhibits characteristics of overactive T cells, increased IL-17 production, and increased lung neutrophil to macrophage ratios. Two reoccurring genetic components in sarcoidosis are NOD2, an intracellular pattern recognition receptor, and ITCH, a HECT E3 ubiquitin ligase. NOD2 detects muramyl dipeptide (MDP), a breakdown product from peptidoglycan in gram-positive bacterial cell walls. Upon MDP sensing and activation, NOD2 forms a complex with RIP2 to signal into the IKK complex, and ultimately lead to NF-κB signaling. GWAS studies have shown gain of function mutations in NOD2 contribute to overactivation of the pathway. While this pathway is most suspect in predisposition to sarcoidosis, human loss of ITCH has been linked to early onset sarcoidosis. ITCH has a role in down regulation of NOD2-mediated NF-κB signaling through K63 ubiquitination of Rip2. Overactivation of IKKs has furthermore been suspect in contributing to other disease states. We have discovered a novel phosphorylation site on ITCH, and on a similar HECT E3 ubiquitin ligase, Nedd4. Phosphorylation at these sites impairs ubiquitin ligase activity. Taken together, these findings suggest that gain of function NOD2 polymorphisms may result in ITCH impairment through posttranslational modification by IKKs. We hypothesize that IKK-mediated disruption of ITCH leads to hyper-activation of inflammatory status. We are proposing biochemical evaluation of phosphorylation at this site. We also propose a genetic experiment to determine the role of aberrant TNF signaling in the pathogenesis of ITCH-driven sarcoidosis in a murine model. These studies will provide mechanistic insights in ITCH and NEDD4 that may facilitate a better understanding of sarcoidosis and treatment efficacies.

描述（由申请人提供）：结节病是一种遗传性炎症性疾病，可出现在淋巴结、眼睛和皮肤组织中，但最常见于肺部。这种慢性肉芽肿性疾病仍然是一种病因不明的疾病，但表现出特征。结节病中两个反复出现的遗传成分是 NOD2（一种细胞内模式识别）。 NOD2 是一种 HECT E3 泛素连接酶，可检测壁酰二肽 (MDP)，这是革兰氏阳性细菌细胞壁中肽聚糖的分解产物。在 MDP 感应和激活后，NOD2 与 RIP2 形成复合物，向 IKK 复合物发出信号。，并最终导致 NF-κB 信号传导，GWAS 研究表明，NOD2 的功能突变会导致该通路的过度激活。在结节病的易感性中，人类 ITCH 的缺失与早期发病的结节病有关，ITCH 通过 Rip2 的 K63 泛素化下调 NOD2 介导的 NF-κB 信号传导，此外还怀疑 IKK 的过度激活会导致其他疾病。我们在 ITCH 和类似的 HECT E3 泛素连接酶 Nedd4 上发现了一个新的磷酸化位点。综上所述，这些研究结果表明，NOD2 多态性的功能增强可能会通过 IKK 的翻译后修饰导致 ITCH 损伤，从而导致炎症状态的过度激活。我们还提出了一项基因实验来确定异常的 TNF 信号在 ITCH 驱动的结节病发病机制中的作用。这些研究将提供 ITCH 和 NEDD4 的机制见解，可能有助于更好地了解结节病和治疗效果。