Ipaf signaling in innate immunity

描述(由申请人提供)：病原体的先天免疫检测依赖于对保守的病原体相关分子模式(PAMPs)的识别。Toll样受体(Toll-like Receptor，TLR)介导的IPS、脂肽、鞭毛蛋白等分子的识别为我们提供了一种天然免疫系统识别PAMPs的模型。有24个NOD/NALP蛋白参与了类似的过程，并遵循TLR范式，但识别细胞质而不是细胞外的PAMP。NOD1和NOD2对细胞质内的细菌肽聚糖做出反应，可能对志贺氏菌和李斯特菌等细菌的细胞内感染做出反应。NOD/NALP家族成员的突变与炎性调节失调疾病相关：NOD2基因多态增加了克罗恩病的风险，而NalpS突变导致了一系列以炎症反应过度激活为特征的综合征。在本提案中，我们将重点介绍NOD/NALP家族成员IPAF。IPAF激活免疫细胞中的核因子-kappaB和Caspase1。它是Caspase1激活和随后由鼠伤寒沙门氏菌感染引起的巨噬细胞死亡所必需的。我们将通过RIP2和ASC定义知之甚少的IPAF信号通路。将确定IPAF及其信号伙伴之间的分子蛋白质-蛋白质相互作用，并确定RIP2和ASC对两种输出(NF-kappaB和Caspase 1)的贡献。我们将表征沙门氏菌介导的IPAF激活，并确定这是否如预测的那样促进炎症反应，或者细菌是否为了自己的利益而颠覆了这种固有反应。这些研究将确定通过IPAF识别巨噬细胞PAMP的功能，并确定沙门氏菌是否进化了破坏旨在摧毁它们的机制的策略。从IPAF信号研究中获得的知识将广泛适用于其他NOD/NALP蛋白及其对免疫防御的调节。这些见解将适用于广泛的炎症性和传染性疾病。

DESCRIPTION (provided by applicant): Innate immune detection of pathogens relies upon recognition of conserved pathogen associated molecular patterns (PAMPs). Toll-like receptor (TLR) mediated recognition of IPS, lipopeptides, flagellin and other molecules has provided us with a model of recognition of PAMPs by the innate immune system. There are 24 Nod/Nalp proteins that are involved in similar processes and follow the TLR paradigm, but recognize cytoplasmic rather than extracellular PAMPs. Nodi and Nod2 respond to bacterial peptidoglycan within the cytoplasmic compartment, likely responding to intracellular infections by bacteria such as Shigella and Listeria. Mutations in Nod/Nalp family members are associated with diseases of inflammatory dysregulation: Nod2 polymorphisms increase the risk of Crohn's disease while NalpS mutations cause a spectrum of syndromes characterized by hyperactivation of inflammatory responses. In this proposal we will focus on Ipaf, a Nod/Nalp family member. Ipaf activates NF-KappaB and Caspase 1 in immune cells. It is required for Caspase 1 activation and subsequent macrophage cell death caused by infection with Salmonella typhimurium. We will define the poorly understood Ipaf signaling pathway through Rip2 and ASC. The molecular protein-protein interactions between Ipaf and its signaling partners will be determined, and the contribution of Rip2 and ASC to the two outputs (NF-KappaB and Caspase 1) will be determined. We will characterize Salmonella mediated Ipaf activation and determine if this acts as predicted to promote inflammatory responses, or if the bacteria have subverted this innate response to their own benefit. These studies will define the function of macrophage PAMP recognition through Ipaf and determine if Salmonella has evolved strategies to corrupt the very mechanism designed to destroy them. Knowledge gained from the study of Ipaf signaling will be broadly applicable to other Nod/Nalp proteins and their regulation of immune defenses. These insights will apply to a broad range of inflammatory and infectious disease.