Human RNF213, which encodes the protein mysterin, is a known susceptibility gene for moyamoya disease (MMD), a cerebrovascular condition with occlusive lesions and compensatory angiogenesis. Mysterin mutations, together with exposure to environmental trigger factors, lead to an elevated stroke risk since childhood. Mysterin is induced during cell stress, to function as cytosolic AAA+ ATPase and ubiquitylation enzyme. Little knowledge exists, in which context mysterin is needed. Here, we found that genetic ablation of several mitochondrial matrix factors, such as the peptidase ClpP, the transcription factor Tfam, as well as the peptidase and AAA+ ATPase Lonp1, potently induces Rnf213 transcript expression in various organs, in parallel with other components of the innate immune system. Mostly in mouse fibroblasts and human endothelial cells, the Rnf213 levels showed prominent upregulation upon Poly(I:C)-triggered TLR3-mediated responses to dsRNA toxicity, as well as upon interferon gamma treatment. Only partial suppression of Rnf213 induction was achieved by C16 as an antagonist of PKR (dsRNA-dependent protein kinase). Since dysfunctional mitochondria were recently reported to release immune-stimulatory dsRNA into the cytosol, our results suggest that mysterin becomes relevant when mitochondrial dysfunction or infections have triggered RNA-dependent inflammation. Thus, MMD has similarities with vasculopathies that involve altered nucleotide processing, such as Aicardi-Goutières syndrome or systemic lupus erythematosus. Furthermore, in MMD, the low penetrance of RNF213 mutations might be modified by dysfunctions in mitochondria or the TLR3 pathway.

中文翻译：

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线粒体ClpP，Lonp1和Tfam的丢失会触发Rnf213的转录诱导，Rnf213是烟雾病的易感性因子。

人类RNF213，其编码蛋白mysterin，为烟雾病（MMD），闭塞性病变和血管发生代偿脑血管病症的已知的易感基因。自童年以来，Mysterin突变以及与环境触发因素的接触导致中风风险升高。神秘素在细胞应激期间被诱导，起细胞溶质AAA + ATPase和泛素化酶的作用。几乎没有知识，在这种情况下需要mysterin。在这里，我们发现几种线粒体基质因子（例如肽酶ClpP，转录因子Tfam以及肽酶和AAA + ATPase Lonp1）的遗传消融均能有效诱导Rnf213转录本在各种器官中的表达，与先天免疫系统的其他组成部分平行。Rnf213水平主要在小鼠成纤维细胞和人内皮细胞中，在Poly（I：C）触发的TLR3介导的dsRNA毒性反应以及干扰素γ处理后显示出明显的上调。仅部分抑制Rnf213通过C16作为PKR（dsRNA依赖性蛋白激酶）的拮抗剂实现了诱导。由于最近报道了功能异常的线粒体将免疫刺激性dsRNA释放到细胞质中，因此我们的结果表明，当线粒体功能异常或感染触发RNA依赖性炎症时，Mysterin变得相关。因此，MMD与血管病变有相似之处，血管病变涉及改变的核苷酸加工过程，例如艾卡迪－古蒂雷斯综合症或系统性红斑狼疮。此外，在MMD中，线粒体功能障碍或TLR3通路可能会改变RNF213突变的低渗透性。