Activation of innate immunity by mitochondrial dsRNA in mouse cells lacking p53 protein

RNA. 2019 Jun;25(6):713-726. doi: 10.1261/rna.069625.118. Epub 2019 Mar 20.

Abstract

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.

Keywords: RNase L; innate immunity; mitochondrial dsRNA; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / deficiency
  • Adenosine Deaminase / genetics*
  • Adenosine Deaminase / immunology
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • DEAD Box Protein 58 / genetics*
  • DEAD Box Protein 58 / immunology
  • Embryo, Mammalian
  • Endoribonucleases / genetics
  • Endoribonucleases / immunology
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Immunity, Innate / genetics*
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / immunology
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteins / genetics
  • Proteins / immunology
  • RNA, Double-Stranded / genetics*
  • RNA, Double-Stranded / immunology
  • RNA, Mitochondrial / genetics*
  • RNA, Mitochondrial / immunology
  • RNA-Binding Proteins
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / immunology

Substances

  • Carrier Proteins
  • Ifit1 protein, mouse
  • Ifit3 protein, mouse
  • Interferon Regulatory Factor-7
  • Intracellular Signaling Peptides and Proteins
  • Irf7 protein, mouse
  • Proteins
  • RNA, Double-Stranded
  • RNA, Mitochondrial
  • RNA-Binding Proteins
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Endoribonucleases
  • 2-5A-dependent ribonuclease
  • ADAR1 protein, mouse
  • Adenosine Deaminase
  • Ddx58 protein, mouse
  • Ifih1 protein, mouse
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1