Cited by 2,627Inflammasome and immune disordersinterferon and immune responsesImmune Response and Inflammation

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AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

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Hornung, Veit, Ablasser, Andrea, Charrel-Dennis, Marie, Bauernfeind, Franz, Horvath, Gabor, Caffrey, Daniel. R., Latz, Eicke, Fitzgerald, Katherine A.·2009·Nature

DOI 10.1038/nature07725PMC PMC2726264

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Abstract

The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.

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Authors: Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D. R., Latz, E., & Fitzgerald, K. A.
Affiliations: University of Massachusetts Chan Medical School (US)
Pfizer (United States) (US)
Corresponding author: Hornung, Veit
Fitzgerald, Katherine A.
ORCID: Hornung, Veit
Ablasser, Andrea
Horvath, Gabor
Latz, Eicke
Fitzgerald, Katherine A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-01-21
Volume: 458
Issue: 7237
Pages: 514-518
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07725
PMC: PMC2726264
OpenAlex: W2042816890
Cited by: 2,627
References: 30
Citations by year: 2026: 108 · 2025: 164 · 2024: 187 · 2023: 152 · 2022: 168 · 2021: 162 · 2020: 158 · 2019: 146 · 2018: 142 · 2017: 137 · 2016: 142 · 2015: 144 · 2014: 147 · 2013: 168 · 2012: 140
FWCI: 66.64
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
MPG.PuRe (Max Planck Society) (submittedVersion)
Funders: National Institute of Allergy and Infectious Diseases (AI065483, R01AI067497, R37AI067497, AI-067497, R01AI065483, R56AI067497)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: AIM2, cytosolic DNA sensing, inflammasome, caspase-1 activation, ASC, pyrin domain, double-stranded DNA, vaccinia virus, NF-κB activation, innate immunity, autoinflammation, autoimmunity, IL-1β, IL-18
MeSH terms: Animals, Cell Line, Cytoskeletal Proteins, Cytosol, DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Inflammation, Nuclear Proteins, Poly dA-dT, Protein Binding, Vaccinia virus, Cell Death, Caspase 1, Apoptosis Regulatory Proteins, Mice, CARD Signaling Adaptor Proteins

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AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

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