Elucidating the Fas-activated inflammation-signaling complex (FISC)

阐明 Fas 激活的炎症信号复合物 (FISC)

• 批准号: 8143491
• 负责人: MIHAIL IORDANOV
• 金额: $ 29.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143491
• 关键词: Adaptor Signaling Protein; Apoptosis; Apoptotic; Biochemical; CASP8 and FADD-like apoptosis regulating protein; CD95 Antigens; Cell Death; Cessation of life; Co-Immunoprecipitations; Complex; Disease; Eczema; Epidermal Growth Factor Receptor; Epithelial Cells; Equilibrium; Extracellular Signal Regulated Kinases; Gene Expression; Homologous Gene; Human; I Kappa B-Alpha; In Situ; Individual; Inflammation; Inflammatory; Inflammatory Response; Ligands; Ligation; MAP Kinase Modules; MAPK8 gene; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Molecular Sieve Chromatography; NF-kappa B; Names; Parkinson Disease; Participant; Pathology; Pathway interactions; Peptide Hydrolases; Phosphotransferases; Proteins; Publishing; RNA Interference; Regulation; Research; Role; Signal Transduction; Signal Transduction Pathway; TNFRSF6 gene; TNFSF6 gene; TRADD gene; Technology; Tumor Necrosis Factor Ligand Superfamily Member 6; Viral; cancer immunotherapy; caspase-8; improved; inhibitor/antagonist; keratinocyte; mitogen-activated protein kinase p38; neuroinflammation; novel strategies; programs; public health relevance; receptor; response; small molecule; stress activated protein kinase

DESCRIPTION (provided by applicant): Engagement of the receptor protein Fas/TNFRSF6 by its ligand, FasL/TNFSF6, triggers apoptotic cells death via well-understood mechanisms involving the assembly of a death-inducing signaling complex (DISC). Fas can also trigger a potent pro-inflammatory program of gene expression in some epithelial cells, such as keratinocytes. The mechanisms of the inflammatory responses to Fas ligation are not understood despite the fact that Fas and FasL have been implicated in inflammatory conditions, from eczematous dermatitis to neuroinflammation in Parkinson's disease. Experimental evidence presented in the Preliminary Studies and our published research suggests that the pro-inflammatory actions of Fas are mediated by a Fas 'signalosome' for which we propose the name 'Fas-activated Inflammation-Signaling Complex' (FISC). In keratinocytes, FISC triggers inflammatory gene expression via signal-transduction pathways that activate the nuclear factor-kappa B (NF-kB), the stress-activated protein kinases (SAPK) JNK and p38 MAP kinase, and the epidermal growth factor receptor (EGFR)-Ras-ERK MAP kinase cascade. Initial biochemical and functional characterization of FISC demonstrates the essential roles of the adaptor protein FADD and the initiator caspase 8 (CASP8) which are also participants in the DISC. However, unlike DISC, FISC does not require the protease activity of CASP8 for its function. The adaptor protein TRADD and the kinase RIP1 were also identified as mediators of the pro-inflammatory responses to Fas engagement. Downstream of FISC, Fas ligation causes the activation of the TGFb-Activated Kinase-1 (TAK1) and the Inhibitor of NF-kB-a (IkBa)-phosphorylating Kinase-b (IKKb). Research in this proposal will characterize, biochemically and functionally, the protein composition of FISC in human epidermal keratinocytes. We will identify downstream effectors of FISC and elucidate the mechanisms of regulation of FISC by FLIP proteins. Finally, we will reveal the mechanisms of crosstalk between the Fas and EGFR pathways. Elucidating the mechanisms of Fas-induced inflammation will improve our understanding of the involvement of Fas in pathology (from eczema to neuroinflammation) and treatment (such as immunotherapy of cancer). PUBLIC HEALTH RELEVANCE: This proposal aims at elucidating the mechanisms of non-apoptotic pro-inflammatory signaling through Fas ligand (FasL/TNSF6) and its receptor Fas/TNFRSF6.

描述（由申请人提供）：由其配体FASL/TNFSF6的受体蛋白FAS/TNFRSF6的参与，通过涉及涉及死亡诱导信号复合物（DISC）组装的机制触发凋亡细胞死亡。 FAS还可以触发某些上皮细胞（例如角质形成细胞）中基因表达的有效促炎程序。尽管FAS和FASL已与炎症状况有关，从昏迷性皮炎到帕金森氏病的神经炎症，但尚不清楚炎症反应对FAS连接的机制。初步研究和我们已发表的研究中提供的实验证据表明，FAS的促炎作用是由FAS“信号体”介导的，我们提出了“ FAS激活的炎症信号复合物”（FISC）。在角质形成细胞中，菲斯克通过信号转导途径触发炎症基因表达，激活核因子-KAPPA B（NF-KB），应激激活的蛋白激酶（SAPK）JNK和P38 MAP激酶以及表皮生长因子（EGFR）-Rasas-rasas-kinase-kinsc kinsc kinscace。 FISC的最初生化和功能表征证明了适配器蛋白FADD和引发剂caspase 8（CASP8）的重要作用，它们也是椎间盘的参与者。但是，与光盘不同，FIS不需要CASP8的蛋白酶活动才能发挥作用。衔接蛋白传统和激酶RIP1也被确定为对FAS参与的促炎反应的介体。 FIS的下游FAS结扎导致TGFB激活的激酶-1（TAK1）和NF-KB-A（IKBA） - 磷酸化激酶-B（IKKB）的抑制剂的激活。该提案中的研究将在生化和功能上表征人类表皮角质形成细胞中菲斯的蛋白质组成。我们将确定FISC的下游效应因子，并阐明Flip蛋白质调节的机理。最后，我们将揭示FAS和EGFR途径之间的串扰机理。阐明FAS诱导的炎症的机制将提高我们对FAS参与病理学（从湿疹到神经炎症）和治疗（例如癌症免疫疗法）的理解。 公共卫生相关性：该提案旨在通过FAS配体（FASL/TNSF6）及其受体FAS/TNFRSF6阐明非凋亡促炎信号的机制。