Mitochondrial double-stranded RNA triggers antiviral signalling in humans

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...

Full description

Saved in:

Bibliographic Details
Published in:	Nature (London) Vol. 560; no. 7717; pp. 238 - 242
Main Authors:	Dhir, Ashish, Dhir, Somdutta, Borowski, Lukasz S., Jimenez, Laura, Teitell, Michael, Rötig, Agnès, Crow, Yanick J., Rice, Gillian I., Duffy, Darragh, Tamby, Christelle, Nojima, Takayuki, Munnich, Arnold, Schiff, Manuel, de Almeida, Claudia Ribeiro, Rehwinkel, Jan, Dziembowski, Andrzej, Szczesny, Roman J., Proudfoot, Nicholas J.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-08-2018 Nature Publishing Group
Subjects:	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 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
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6570621
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-018-0363-0