Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation

Cell. 2018 Feb 8;172(4):797-810.e13. doi: 10.1016/j.cell.2017.12.016. Epub 2018 Jan 25.

Abstract

Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.

Keywords: Aicardi-Goutières syndrome; Alu; IFIH1; MDA5; auto-inflammation; innate immunity; retroelement.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Alu Elements / immunology*
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology*
  • Autoimmune Diseases of the Nervous System / pathology
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / immunology*
  • Muramidase
  • Nervous System Malformations / genetics
  • Nervous System Malformations / immunology*
  • Nervous System Malformations / pathology
  • Peptide Fragments
  • Protein Multimerization / genetics
  • Protein Multimerization / immunology*
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / immunology*
  • Self Tolerance*
  • THP-1 Cells

Substances

  • Peptide Fragments
  • RNA, Double-Stranded
  • hen egg lysozyme peptide (115-129)
  • Muramidase
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Aicardi-Goutieres syndrome