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Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation
Open accessAbstract
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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“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.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [98]
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Metadata
- 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)
- PMC
- PMC5807104
- 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
- bronze
- doi.org
- Licence
- 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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