The mitochondrial intermembrane space protein Smac/DIABLO in signal transduction and immune response

线粒体膜间隙蛋白 Smac/DIABLO 在信号转导和免疫反应中的作用

• 批准号: 456220843
• 负责人: Professor Dr. Georg Häcker
• 金额: --
• 依托单位: Department für Medizinische Mikrobiologie, Virologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456220843?language=en
• 关键词: mitochondrial; intermembrane; space; protein; Smac

Smac is a mitochondrial intermembrane space protein that is released and that facilitates caspase-activation during apoptosis. A number of other, potential, cytosolic functions of Smac can be inferred based on experimental cytosolic expression of Smac and on the use of small-molecule ‘Smac-mimetics’ but there is very little evidence of a function of Smac-protein outside cell death. It is becoming evident that the apoptosis signalling apparatus can also be activated only to a low level, where some signalling events can be detected but the cell stays alive. We have recently found that such ‘sub-lethal’ mitochondrial apoptosis signalling (‘minority MOMP’) is a feature of infection of human and mouse cells with any of several bacterial and viral pathogens tested. Our data suggest that this signalling is a mechanism of cell alert and plays a role in anti-microbial host defence. Our recent data further suggest that Smac is important in mitochondrial sub-lethal apoptosis signalling. We have tested for a role of Smac in infection in vitro with Helicobacter pylori and have found evidence that Smac is in this infection released during minority MOMP, is required for the activation of alternative NF-kappaB and contributes to cytokine production by epithelial cells. We propose that Smac-release is a general feature of minority MOMP, and that Smac has a signalling function in the detection of the infection of non-professional immune cells by pathogens. In this project we will test this hypothesis. We will analyse the relative release of Smac and cytochrome c during situations of minority MOMP and will establish whether it is individual mitochondria or more of the mitochondrial network releasing these proteins. We will further endeavour to distinguish the relative roles of cytochrome c and Smac for the biological effects of minority MOMP. We will investigate Smac-dependent signalling in the cytosol, focussing on events consecutive to the neutralisation of inhibitor of apoptosis proteins and will more thoroughly test for the secretion of cytokines and bacterial containment. We have made a Smac-deficient mouse line and will use intestinal organoids from these mice and perform infections of the mice with Helicobacter felis and Chlamydia muridarum to understand the contribution of Smac to the immune response to bacterial infection. Our data suggest that Smac has signalling functions outside apoptotic cell death in the initiation of an immune reaction, and we hope to be able here to work out signalling pathways and physiological roles of such functions.

Smac是一种线粒体膜间隙蛋白，在细胞凋亡过程中释放并促进caspase激活。基于Smac的实验胞浆表达和小分子“Smac模拟物”的使用，可以推断出Smac的许多其他潜在的细胞质功能，但很少有证据表明Smac蛋白在细胞死亡外具有功能。越来越明显的是，凋亡信号装置也只能被激活到一个低水平，其中一些信号事件可以被检测到，但细胞仍然存活。我们最近发现，这种“亚致死”线粒体凋亡信号（“少数MOMP”）是人类和小鼠细胞感染几种细菌和病毒病原体的一个特征。我们的数据表明，这种信号是一种细胞警报机制，在抗微生物宿主防御中发挥作用。我们最近的数据进一步表明，Smac在线粒体亚致死细胞凋亡信号传导中很重要。我们已经测试了Smac在幽门螺杆菌体外感染中的作用，并发现证据表明Smac在这种感染中在少数MOMP期间释放，是激活替代NF-kappaB所必需的，并有助于上皮细胞产生细胞因子。我们认为Smac释放是少数MOMP的普遍特征，并且Smac在检测病原体对非专业免疫细胞的感染中具有信号功能。在这个项目中，我们将检验这个假设。我们将分析在少数MOMP情况下Smac和细胞色素c的相对释放，并将确定是单个线粒体还是更多的线粒体网络释放这些蛋白质。我们将进一步努力区分细胞色素c和Smac在少数MOMP生物学效应中的相对作用。我们将研究细胞质中smac依赖的信号传导，重点关注与细胞凋亡蛋白抑制剂中和相关的事件，并将更彻底地测试细胞因子的分泌和细菌遏制。我们已经制作了一个Smac缺陷小鼠系，并将使用这些小鼠的肠道类器官，并对小鼠进行felis Helicobacter和muridarum衣原体感染，以了解Smac对细菌感染的免疫反应的贡献。我们的数据表明，Smac在启动免疫反应的凋亡细胞死亡之外具有信号功能，我们希望能够在这里找出这种功能的信号通路和生理作用。