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Mitochondrial double-stranded RNA triggers antiviral signalling in humans

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cris.lastimport.scopus2024-02-12T19:28:59Z
dc.abstract.enMitochondria are descendants of endosymbiotic bacteria and retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, mitochondrial DNA is subjected to bidirectional transcription that generates overlapping transcripts, which are capable of forming long double-stranded RNA structures1,2. However, to our knowledge, mitochondrial double-stranded RNA has not been previously characterized in vivo. Here we describe the presence of a highly unstable native mitochondrial double-stranded RNA species at single-cell level and identify key roles for the degradosome components mitochondrial RNA helicase SUV3 and polynucleotide phosphorylase PNPase in restricting the levels of mitochondrial double-stranded RNA. Loss of either enzyme results in massive accumulation of mitochondrial double-stranded RNA that escapes into the cytoplasm in a PNPase-dependent manner. This process engages an MDA5-driven antiviral signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in the gene PNPT1, which encodes PNPase, display mitochondrial double-stranded RNA accumulation coupled with upregulation of interferon-stimulated genes and other markers of immune activation. The localization of PNPase to the mitochondrial inter-membrane space and matrix suggests that it has a dual role in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms that have evolved to protect vertebrates against microbial and viral attack.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorTamby, Christelle
dc.contributor.authorNojima, Takayuki
dc.contributor.authorDziembowski, Andrzej
dc.contributor.authorRice, Gillian I.
dc.contributor.authorDuffy, Darragh
dc.contributor.authorRötig, Agnès
dc.contributor.authorCrow, Yanick J.
dc.contributor.authorJimenez, Laura
dc.contributor.authorTeitell, Michael
dc.contributor.authorDhir, Ashish
dc.contributor.authorDhir, Somdutta
dc.contributor.authorSzczęsny, Roman
dc.contributor.authorBorowski, Łukasz
dc.contributor.authorSchiff, Manuel
dc.contributor.authorAlmeida, Claudia Ribeiro de
dc.contributor.authorMunnich, Arnold
dc.contributor.authorRehwinkel, Jan
dc.contributor.authorProudfoot, Nicholas J.
dc.date.accessioned2024-01-25T12:40:43Z
dc.date.available2024-01-25T12:40:43Z
dc.date.issued2018
dc.description.financeNie dotyczy
dc.description.volume560
dc.identifier.doi10.1038/S41586-018-0363-0
dc.identifier.issn0028-0836
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112674
dc.identifier.weblinkhttps://www.nature.com/articles/s41586-018-0363-0
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofNature
dc.relation.pages238-242
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleMitochondrial double-stranded RNA triggers antiviral signalling in humans
dc.typeJournalArticle
dspace.entity.typePublication