Journal Article

Mitochondrial double-stranded RNA triggers antiviral signalling in humans

Teitell, Michael, Nojima, Takayuki, Crow, Yanick J., Tamby, Christelle, Borowski, Lukasz S., Rice, Gillian I., Dziembowski, Andrzej, Rehwinkel, Jan, Jimenez, Laura, Duffy, Darragh, Dhir, Somdutta, Dhir, Ashish, Proudfoot, Nicholas J., Schiff, Manuel, Munnich, Arnold, Szczesny, Roman J., de Almeida, Claudia Ribeiro, Rötig, Agnès

2018

Overview

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 structures 1 , 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. Mitochondrial double-stranded RNA can induce an interferon response if released into the cytoplasm, but self-recognition is prevented by SUV3 helicase and PNPase exoribonuclease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/89 / 14 / 14/19 / 14/28 / 38 / 38/61 / 45 / 45/91 / 631/250/262/2106 / 631/337/1645/501 / Accumulation / Activation / Animals / Antiviral drugs / Bacteria / bcl-2 Homologous Antagonist-Killer Protein - metabolism / bcl-2-Associated X Protein - metabolism / Bioinformatics / Biological response modifiers / Cytoplasm / DEAD-box RNA Helicases - deficiency / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Deoxyribonucleic acid / Diabetes / DNA / DNA helicase / Double-stranded RNA / Endoribonucleases - metabolism / Enzymes / Exoribonucleases - deficiency / Exoribonucleases - genetics / Exoribonucleases - metabolism / Gene Expression Regulation - immunology / Genes / Genetic aspects / Genomes / Genomics / HeLa Cells / Herpesvirus 1, Human - genetics / Herpesvirus 1, Human - immunology / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunologic research / Immunology / Immunotherapy / Indigenous species / Infections / Interferon / Interferon Type I - antagonists & inhibitors / Interferon Type I - immunology / Interferon-Induced Helicase, IFIH1 - metabolism / Letter / Life Sciences / Localization / Mammals / Metabolism / Mice / Mice, Inbred C57BL / Microorganisms / Microscopy / Mitochondria / Mitochondrial DNA / multidisciplinary / Multienzyme Complexes - metabolism / Mutation / Phosphorylase / Physiological aspects / Polynucleotide phosphorylase / Polyribonucleotide Nucleotidyltransferase - metabolism / Ribonuclease / Ribonucleic acid / RNA / RNA helicase / RNA Helicases - metabolism / RNA polymerase / RNA, Double-Stranded - immunology / RNA, Mitochondrial - immunology / Science / Science (multidisciplinary) / Signal transduction / Signaling / Single-Cell Analysis / Transcription / Transcription (Genetics) / Vertebrates / Viral infections