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Deciphering the function of actin remodeling in NLR-mediated innate immune sensing

破译肌动蛋白重塑在 NLR 介导的先天免疫传感中的功能

基本信息

批准号：
278109143
负责人：
Professor Dr. Thomas Kufer
金额：
--
依托单位：
Institut für Zellbiologie und Immunologie (IZI)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/278109143?language=en
关键词：
Deciphering function actin remodeling NLR

项目摘要

Innate immunity depends on sensing of conserved pathogen derived structures, referred to as microbe associated molecular patterns (MAMPs) by pattern-recognition receptors (PRRs) in the host cell. Members of the NLR-protein family are important PRRs that refer inflammatory responses upon activation by microbial stimuli. We have a long standing interesting in the functional characterization of mammalian NLR proteins. A particular focus of our work lies on the NLR-protein NOD1 that senses bacterial peptidoglycan. Although the main concepts of NOD1 activation and signaling are emerging, our knowledge on the cell biology of NOD1 and its fine regulation is still quite limited. We have shown that NOD1 co-localizes with F-actin in the host cell and in more recent work using HT-screening we now have identified components of the actin regulatory network that contribute to NOD1-mediated inflammatory responses. Notably, many invasive bacteria, that can activate NOD1, can simultaneously affect actin dynamics by the action of virulence proteins which often target small GTPases that indirectly regulate F-actin dynamics. Recent findings, show that subversion of host Rho GTPase activity by bacterial effectors is linked to NOD1-mediated inflammatory responses. Our recent study revealed that F-actin dynamic is important for NOD1 signaling in human cells. We have identified key components of the regulation of F-actin dynamic, namely the phosphatase SSH1 and its substrate cofilin, as important molecular mediators of this function. This leads us to propose that these proteins are involved in integrating subversion of actin remodeling by bacterial effectors and MAMP sensing. Here we will expand on our recent findings and address open questions, such as the role of the different orthologs of cofillin and SSH in NLR-meditated responses. Most importantly, we will elucidate the underlying molecular details by identification of the network of proteins involved in this novel pathway. Finally, will address if activation of NOD1 changes actin polymerization in human cells and if this contributes to cell-autonomous anti-bacterial responses. Moreover, we will expand our initial observation made with Shigella flexneri as infection model to other clinically relevant bacterial pathogens and analyze the effect of SSH1/cofilin on additional NOD1-mediated signalling outcomes such as autophagy. The indirect sensing of bacterial activity by guarding host cell actin dynamics is a novel concept in the field of innate immunity in mammals. Deciphering the role of F-actin remodelling in NLR-mediated innate immunity will provide important novel insights into the biology of host-pathogen interactions and in the long run will set the stage for the development of novel therapeutically strategies to treat inflammatory disorders.

先天免疫依赖于宿主细胞中模式识别受体（PRRs）对保守的病原体衍生结构（称为微生物相关分子模式（MAMPs））的感知。nlr蛋白家族成员是重要的PRRs，涉及微生物刺激激活后的炎症反应。我们对哺乳动物NLR蛋白的功能表征一直很感兴趣。我们工作的一个特别重点在于nlr蛋白NOD1，它能感知细菌肽聚糖。虽然NOD1激活和信号转导的主要概念不断涌现，但我们对NOD1细胞生物学及其精细调控的认识仍然非常有限。我们已经证明NOD1在宿主细胞中与f -肌动蛋白共定位，在最近使用ht筛选的工作中，我们现在已经确定了肌动蛋白调节网络中有助于NOD1介导的炎症反应的成分。值得注意的是，许多可以激活NOD1的侵袭性细菌可以同时通过毒力蛋白的作用影响肌动蛋白动力学，这些毒力蛋白通常靶向间接调节f -肌动蛋白动力学的小gtpase。最近的研究表明，细菌效应物对宿主Rho GTPase活性的破坏与nod1介导的炎症反应有关。我们最近的研究表明，F-actin动态对人类细胞中NOD1信号传导很重要。我们已经确定了F-actin动态调控的关键成分，即磷酸酶SSH1及其底物cofilin，作为该功能的重要分子介质。这使我们提出这些蛋白质参与了细菌效应物和MAMP传感对肌动蛋白重塑的颠覆整合。在这里，我们将扩展我们最近的发现，并解决一些悬而未决的问题，例如cofillin和SSH的不同同源物在nlr冥想反应中的作用。最重要的是，我们将通过鉴定参与这种新途径的蛋白质网络来阐明潜在的分子细节。最后，将讨论NOD1的激活是否会改变人类细胞中的肌动蛋白聚合，以及这是否有助于细胞自主的抗菌反应。此外，我们将把以福氏志贺氏菌为感染模型的初步观察扩展到其他临床相关的细菌病原体，并分析SSH1/cofilin对nod1介导的其他信号转导结果（如自噬）的影响。通过保护宿主细胞肌动蛋白动态来间接感知细菌活性是哺乳动物先天免疫领域的一个新概念。破译f -肌动蛋白重塑在nlr介导的先天免疫中的作用将为宿主-病原体相互作用的生物学提供重要的新见解，从长远来看，将为开发治疗炎症性疾病的新治疗策略奠定基础。