Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease

  • 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.
Metadaten
Author:Jana KeyGND, Antonia Luisa MaletzkoGND, Aneesha KohliORCiD, Suzana Gispert, Sylvia Torres-OdioORCiD, Ilka WittigORCiD, Juliana HeidlerORCiD, Clea BárcenaORCiD, Carlos López-OtínORCiDGND, Yuanjiu LeiORCiD, A. Phillip WestORCiD, Christian MünchORCiDGND, Georg AuburgerORCiDGND
URN:urn:nbn:de:hebis:30:3-813055
DOI:https://doi.org/10.1007/s10048-020-00609-2
ISSN:1364-6753
Parent Title (English):Neurogenetics
Publisher:Springer
Place of publication:Berlin ; Heidelberg
Document Type:Article
Language:English
Date of Publication (online):2020/04/28
Date of first Publication:2020/04/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/02/28
Tag:AAA+ disaggregase; Autoimmune vasculopathy; Innate immunity; Mitochondrial dysfunction; Perrault syndrome; Stroke genetics; Ubiquitin ligase
Volume:21
Issue:3
Page Number:17
First Page:187
Last Page:203
Note:
Open Access funding provided by Projekt DEAL. The study was financed by funds from the Goethe University Medical Faculty.
HeBIS-PPN:517874695
Institutes:Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International