AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC
Open accessAbstract
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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AIM2 has a pyrin domain that allows it to interact with the adaptor protein ASC to form the inflammasome.
“Although distinct from NLRs, AIM2 has a pyrin domain that allows it to interact with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) to form the inflammasome50.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [50]
The AIM2 inflammasome has been shown to recognize cytoplasmic double-stranded DNA (dsDNA) that is not necessarily microbial in origin, resulting in caspase 1 activation and IL-1β secretion.
“The AIM2 inflammasome has been recently shown to recognize cytoplasmic double-stranded DNA (dsDNA) that is not necessarily microbial in origin, resulting in caspase 1 activation and IL-1β secretion48–50.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [50]
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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.
- Venue
- Nature
- Published
- 2009-01-21
- Volume
- 458
- Issue
- 7237
- Pages
- 514-518
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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