Parkin and PINK1 mitigate STING-induced inflammation.
Parkin and PINK1 mitigate STING-induced inflammation.
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DOI：
10.1038/s41586-018-0448-9
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发表时间：
2018-09
期刊：
影响因子：
64.8
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Sliter DA;Martinez J;Hao L;Chen X;Sun N;Fischer TD;Burman JL;Li Y;Zhang Z;Narendra DP;Cai H;Borsche M;Klein C;Youle RJ
尽管帕金森病（PD）患者的血清显示多种促炎细胞因子（包括IL-6、TNFα、IL-1β和IFNβ1）水平升高，但炎症是否导致神经元损失或其结果仍不清楚。E3泛素连接酶Parkin和泛素激酶PINK 1的突变导致早发性PD。PINK 1和Parkin在相同的生化途径中工作，通过一种选择性的自噬形式（称为线粒体自噬）从培养细胞和动物模型中去除受损的线粒体。然而，线粒体自噬在体内的作用尚不清楚，部分原因是缺乏PINK 1或Parkin的小鼠没有实质性的PD相关表型。由于线粒体应激可导致可激活先天免疫的损伤相关分子模式（DAMP）的释放，因此线粒体自噬可减轻炎症。在这里，我们报告了Parkin−/−和PINK 1 −/−小鼠在力竭运动（EE）后以及Parkin−/−;Mutator小鼠中的强烈炎症表型，这些小鼠随着年龄的增长而积累线粒体DNA突变。由EE和mtDNA突变两者引起的炎症通过同时失去STING（I型干扰素对胞质DNA的反应的中心调节物）而被完全拯救。来自黑质腹侧部（SNc）的多巴胺能（DA）神经元的损失和在老年Parkin−/−;Mutator小鼠中观察到的运动缺陷也通过STING的损失而被挽救，这表明炎症促进了这种表型。具有单等位基因和双等位基因帕金突变的人也显示出升高的细胞因子。这些结果支持PINK 1和Parkin介导的线粒体自噬在抑制先天免疫中的作用。
Although serum from Parkinson’s disease (PD) patients displays elevated levels of numerous pro-inflammatory cytokines including IL-6, TNFα, IL-1β, and IFNβ1, whether inflammation contributes to or is a consequence of neuronal loss remains unknown. Mutations in Parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early-onset PD. Working in the same biochemical pathway, PINK1 and Parkin remove damaged mitochondria from cells in culture and in animal models via a selective form of autophagy, called mitophagy. The role of mitophagy in vivo, however, is unclear in part because mice lacking PINK1 or Parkin have no substantial PD-relevant phenotypes. As mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity, mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Parkin−/− and PINK1−/− mice following exhaustive exercise (EE) and in Parkin−/−;Mutator mice, which accumulate mitochondrial DNA mutations with age. Inflammation resulting from both EE and mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I Interferon response to cytosolic DNA. The loss of dopaminergic (DA) neurons from the substantia nigra pars compacta (SNc) and the motor defect observed in aged Parkin−/−;Mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic Parkin mutations also display elevated cytokines. These results support a role for PINK1- and Parkin-mediated mitophagy in restraining innate immunity.
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