RESUMO
Viral and cellular double-stranded RNA (dsRNA) is recognized by cytosolic innate immune sensors, including RIG-I-like receptors. Some cytoplasmic dsRNA is commonly present in cells, and one source is mitochondrial dsRNA, which results from bidirectional transcription of mitochondrial DNA (mtDNA). Here we demonstrate that Trp53 mutant mouse embryonic fibroblasts contain immune-stimulating endogenous dsRNA of mitochondrial origin. We show that the immune response induced by this dsRNA is mediated via RIG-I-like receptors and leads to the expression of type I interferon and proinflammatory cytokine genes. The mitochondrial dsRNA is cleaved by RNase L, which cleaves all cellular RNA including mitochondrial mRNAs, increasing activation of RIG-I-like receptors. When mitochondrial transcription is interrupted there is a subsequent decrease in this immune-stimulatory dsRNA. Our results reveal that the role of p53 in innate immunity is even more versatile and complex than previously anticipated. Our study, therefore, sheds new light on the role of endogenous RNA in diseases featuring aberrant immune responses.
Assuntos
Adenosina Desaminase/genética , Proteína DEAD-box 58/genética , Imunidade Inata/genética , RNA de Cadeia Dupla/genética , RNA Mitocondrial/genética , Proteína Supressora de Tumor p53/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenosina Desaminase/deficiência , Adenosina Desaminase/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteína DEAD-box 58/imunologia , Embrião de Mamíferos , Endorribonucleases/genética , Endorribonucleases/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas/genética , Proteínas/imunologia , RNA de Cadeia Dupla/imunologia , RNA Mitocondrial/imunologia , Proteínas de Ligação a RNA , Transcrição Gênica , Transfecção , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/imunologiaRESUMO
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in dsRNA. ADAR editing in pre-mRNAs recodes open reading frames and alters splicing, mRNA structure and interactions with miRNAs. Here, we review ADAR gene expression, splice forms, posttranslational modifications, subcellular localizations and functions of ADAR protein isoforms. ADAR1 edits cellular dsRNA to prevent aberrant activation of cytoplasmic antiviral dsRNA sensors; ADAR1 mutations lead to aberrant expression of interferon in Aicardi Goutières syndrome (AGS), a human congenital encephalopathy. We review related studies on mouse Adar1 mutant phenotypes, their rescues by preventing signaling from the antiviral RIG-I-like Sensors (RLRs), as well as Adar1 mechanisms in innate immune suppression and other roles of Adar1, including editing-independent effects. ADAR2, expressed primarily in CNS, edits glutamate receptor transcripts; regulation of ADAR2 activity in response to neuronal activity mediates homeostatic synaptic plasticity of vertebrate AMPA and kainite receptors. In Drosophila, synapses and synaptic proteins show dramatic decreases at night during sleep; Drosophila Adar, an orthologue of ADAR2, edits hundreds of mRNAs; the most conserved editing events occur in transcripts encoding synapse-associated proteins. Adar mutant flies exhibit locomotion defects associated with very increased sleep pressure resulting from a failure of homeostatic synaptic processes. A study on Adar2 mutant mice identifies a new role in circadian rhythms, acting indirectly through miRNAs such as let-7 to modulate levels of let-7 target mRNAs; ADAR1 also regulates let-7 miRNA processing. Drosophila ADAR, an orthologue of vertebrate ADAR2, also regulates let-7 miRNA levels and Adar mutant flies have a circadian mutant phenotype.