Cited by 449interferon and immune responsesImmune Response and InflammationRNA regulation and disease

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

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Ahmad, Sadeem, Mu, Xin, Yang, Fei, Greenwald, Emily, Park, Ji Woo, Jacob, Etai, Zhang, Cheng-Zhong, Hur, Sun·2018·Cell

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.

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Crossref · 10.1016/j.cell.2017.12.016

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  • Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation.

    “Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation50, 51, 98.”

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Authors
Ahmad, S., Mu, X., Yang, F., Greenwald, E., Park, J. W., Jacob, E., Zhang, C.-Z., & Hur, S.
Affiliations
  • Boston Children's Hospital (US)
  • Boston College (US)
  • Broad Institute (US)
Corresponding author
Hur, Sun
Venue
Cell
Publisher
Elsevier BV
Published
2018-02
Volume
172
Issue
4
Pages
797-810.e13
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2784999778
Cited by
449
References
46
Citations by year
2026: 58 · 2025: 54 · 2024: 45 · 2023: 44 · 2022: 43 · 2021: 85 · 2020: 49 · 2019: 38 · 2018: 33
FWCI
22.02
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cancer Research Institute
  • Burroughs Wellcome Fund
  • National Institutes of Health (R01AI106912, R21AI130791, R01AI111784)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
MDA5, Aicardi-Goutières syndrome, double-stranded RNA, self-tolerance, RNA duplex structure
MeSH terms
A549 Cells, Interferon-Induced Helicase, IFIH1, THP-1 Cells, Humans, Inflammation, Muramidase, Nervous System Malformations, Peptide Fragments, RNA, Double-Stranded, Self Tolerance, Alu Elements, Autoimmune Diseases of the Nervous System, Protein Multimerization

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