The role of mitochondrial CLPP protease in the regulation of innate immunity

由于其细菌来源，线粒体含有许多有效的免疫刺激损伤相关分子模式（DAMP），包括低甲基化mtDNA、dsRNA和甲酰化蛋白，其可以激活先天免疫系统，特别是I型干扰素（IFN-I）。细胞暴露于mtDNA长期以来一直被认为是免疫刺激性的，并且mtDNA释放到胞质溶胶中可以激活几种模式识别受体（PPR）以触发各种先天免疫应答。近年来，人们越来越认识到，除了支持由PRR协调的抗病毒反应外，线粒体DAMP的不受控制和过度释放有助于在许多炎症和自身免疫性疾病以及缺血性心脏病和癌症中观察到的失调过程。虽然最近研究中的新证据揭示了更多关于线粒体在先天免疫调节中的作用，但我们留下的问题多于答案，本项目提案旨在回答其中一些问题。我们的初步数据表明，mtDNA的释放可能是一个高度调节的过程，不依赖于线粒体功能障碍或物理损伤的水平。相反，我们表明，线粒体基质蛋白酶CLPP，线粒体质量控制机制的一部分，防止释放线粒体DAMPs和IFN-I反应的激活。此外，体内CLPP缺陷提供了先天免疫应答和全身代谢控制之间的串扰的提示，这是以前没有研究过的。使用细胞和体内模型的组合，我们的目标是发现这些过程背后的分子机制，以精确地映射线粒体DAMP及其信号级联。因此，该项目将使我们能够了解CLPP蛋白酶在保护细胞免受线粒体DAMPS释放方面的管家作用。我们相信，它们还将提供线粒体在不同病理中激活先天免疫反应的作用的急需知识，并有望发现潜在的治疗靶点。

Due to its bacterial origin mitochondria contain numerous potent immunostimulatory damage-associated molecular patterns (DAMPs), including hypomethylated mtDNA, dsRNA and formylated proteins, that can activate the innate immune system, type I interferon (IFN-I) in particular. The exposure of cells to mtDNA has long been known to be immunostimulatory and the release of mtDNA into the cytosol can activate several pattern recognition receptors (PPRs) to trigger a variety of innate immune responses. In recent years it was increasingly recognized that besides supporting the antiviral response orchestrated by PRRs, uncontrolled and excessive release of mitochondrial DAMPs contributes to the dysregulated process observed in numerous inflammatory and autoimmune conditions, as well as in ischemic heart disease and cancer. Whilst new evidence in recent studies has revealed more about the role of mitochondria in the modulation of innate immunity, we are left with more questions than answers, and this project proposal aims to answer some of them. Our preliminary data suggest that mtDNA release might be a highly regulated process that does not depend on the level of mitochondrial dysfunction or physical damage. Instead, we show that mitochondrial matrix protease CLPP, part of mitochondrial quality control machinery, guards against the release of mitochondrial DAMPs and the activation of IFN-I response. Furthermore, CLPP deficiency in vivo provides hints for the crosstalk between innate immunity responses and control of systemic metabolism that were previously not investigated. Using a combination of cell and in vivo models we aim to discover molecular mechanisms behind these processes, to precisely map mitochondrial DAMPs and their signalling cascades. Therefore, this project will allow us to understand the housekeeping role of CLPP protease in guarding cells against the release of mitochondrial DAMPS. We believe they will also provide much-needed knowledge of the role of mitochondria in the activation of innate immunity responses in different pathologies, with prospective to uncover potential therapeutic targets.