Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease
Rattachement africain : de, us, es. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease
- Date Crossref
- 28/04/2020
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Goethe University Frankfurt pays non établi dans la noticeUniversité ou école supérieure
-
Texas A&M University Department of Microbial Pathogenesis and Immunology pays non établi dans la noticeUniversité ou école supérieure
-
Universidad de Oviedo pays non établi dans la noticeUniversité ou école supérieure
-
Goethe University Medical School Experimental Neurology pays non établi dans la noticeUniversité ou école supérieure
-
Faculty of Biosciences pays non établi dans la noticeUniversité ou école supérieure
-
Goethe-University Hospital Functional Proteomics Group pays non établi dans la noticeUniversité ou école supérieure
-
Instituto Universitario de Oncología Facultad de Medicina pays non établi dans la noticeStructure de recherche
Goethe University Frankfurt, Department of Microbial Pathogenesis and Immunology — Texas A&M University et Universidad de Oviedo, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.