TY  - JOUR
A1  - Key, Jana
A1  - Maletzko, Antonia Luisa
A1  - Kohli, Aneesha
A1  - Gispert, Suzana
A1  - Torres-Odio, Sylvia
A1  - Wittig, Ilka
A1  - Heidler, Juliana
A1  - Bárcena, Clea
A1  - López-Otín, Carlos
A1  - Lei, Yuanjiu
A1  - West, A. Phillip
A1  - Münch, Christian
A1  - Auburger, Georg
T1  - Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease
T2  - Neurogenetics
N2  - 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.
KW  - Perrault syndrome
KW  - Mitochondrial dysfunction
KW  - AAA+ disaggregase
KW  - Ubiquitin ligase
KW  - Stroke genetics
KW  - Innate immunity
KW  - Autoimmune vasculopathy
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/81305
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-813055
SN  - 1364-6753
N1  - Open Access funding provided by Projekt DEAL. The study was financed by funds from the Goethe University Medical Faculty.
VL  - 21
IS  - 3
SP  - 187
EP  - 203
PB  - Springer
CY  - Berlin ; Heidelberg
ER  -