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

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

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Biology Department in Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA, USA.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, MA 02115, USA.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: sun.hur@childrens.harvard.edu.

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

Comment in

PMID:
29395326
PMCID:
PMC5807104
DOI:
10.1016/j.cell.2017.12.016
[Indexed for MEDLINE]
Free PMC Article

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