Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse.
Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse.
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DOI：
10.1007/s10048-021-00657-2
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发表时间：
2021-10
期刊：
影响因子：
2.2
通讯作者：
Auburger G
中科院分区：
文献类型：
--
作者：
Maletzko A;Key J;Wittig I;Gispert S;Koepf G;Canet-Pons J;Torres-Odio S;West AP;Auburger G
线粒体功能障碍可能会激活先天免疫，例如TFAM 突变体或改变的线粒体自噬中线粒体 DNA 的异常处理。最近的报告表明，小鼠线粒体基质肽酶 ClpP 的缺失也会引发炎症因子的转录上调。在这里，我们研究了两个年龄的 ClpP 缺失小鼠大脑和小鼠胚胎成纤维细胞，利用质谱、亚细胞分级分离、免疫印迹和逆转录酶聚合酶链反应来确定哪些信号通路起作用。几种线粒体未折叠蛋白反应因子在蓝色天然凝胶中显示出积累和迁移改变，尤其是共伴侣 DNAJA3。其线粒体失调也增加了其在细胞核中的线粒体外丰度，考虑到 DNAJA3 调节先天免疫，这是一个相关的观察结果。对 STAT1（一种假定的 DNAJA3 相互作用因子）也进行了类似的观察。不仅转录因子 Stat1/2 表达升高，两个干扰素刺激基因（Ifi44、Gbp3）也表达升高。 RLR 模式识别受体（Ddx58、Ifih1、Oasl2、Trim25）和几种胞质核酸传感器（Ifit1、Ifit3、Oas1b、Ifi204、Mnda）的炎症反应最强。这些因素从幼年起就持续失调，也可能影响人类 Perrault 综合征，其中 ClpP 功能丧失导致早期不孕和耳聋，以及随后广泛的神经退行性疾病。在线版本包含可在 10.1007/s10048-021-00657-2 获取的补充材料。
Mitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration. The online version contains supplementary material available at 10.1007/s10048-021-00657-2.
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