Transcriptomics,Genomics

Dataset Information

158

Mitochondrial dsRNA triggers antiviral signalling in humans


ABSTRACT: Mitochondria 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 capable of forming long double-stranded RNA structures. 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 keyroles for the degradosome components, mitochondrial dsRNA 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 evolved to protect vertebrates against microbial and viral attack. Overall design: We performed J2 IP dsRNA-seq from HeLa cell lysates by immunoprecipitation with anti-dsRNA (J2) mab. Untreated and siCntrl treated HeLa cells were used in the experiment. Experiment was performed in duplicates from HeLa cells treated with siSUV3 and siPNPase. Input RNA samples were ribodepleted with Ribo-Zero rRNA-removal kit. IPed RNA samples were not ribodepleted.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: Nicholas Proudfoot 

PROVIDER: GSE94957 | GEO | 2018-05-03

REPOSITORIES: GEO

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Publications


Mitochondria 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 mitoc  ...[more]

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