Mitochondrial double-stranded RNA triggers antiviral signalling in humans

Ashish Dhir (), Somdutta Dhir, Lukasz S. Borowski, Laura Jimenez, Michael Teitell, Agnès Rötig, Yanick J. Crow, Gillian I. Rice, Darragh Duffy, Christelle Tamby, Takayuki Nojima, Arnold Munnich, Manuel Schiff, Claudia Ribeiro Almeida, Jan Rehwinkel, Andrzej Dziembowski, Roman J. Szczesny () and Nicholas J. Proudfoot ()
Additional contact information
Ashish Dhir: University of Oxford
Somdutta Dhir: University of Oxford
Lukasz S. Borowski: Polish Academy of Sciences
Laura Jimenez: University of California, Los Angeles
Michael Teitell: University of California, Los Angeles
Agnès Rötig: INSERM UMR1163, Institut Imagine
Yanick J. Crow: INSERM UMR1163, Institut Imagine
Gillian I. Rice: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester
Darragh Duffy: Immunobiology of Dendritic Cells, Institut Pasteur
Christelle Tamby: INSERM UMR1163, Institut Imagine
Takayuki Nojima: University of Oxford
Arnold Munnich: INSERM UMR1163, Institut Imagine
Manuel Schiff: INSERM UMR1163, Institut Imagine
Claudia Ribeiro Almeida: University of Oxford
Jan Rehwinkel: University of Oxford
Andrzej Dziembowski: Polish Academy of Sciences
Roman J. Szczesny: Polish Academy of Sciences
Nicholas J. Proudfoot: University of Oxford

Nature, 2018, vol. 560, issue 7717, 238-242

Abstract: 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, 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.

Date: 2018
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DOI: 10.1038/s41586-018-0363-0

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