Letter

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

  • Nature volume 458, pages 514518 (26 March 2009)
  • doi:10.1038/nature07725
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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)1. Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses2,3,4,5,6. 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 genes2,3. 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 IL1β and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein)8 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-κB 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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Acknowledgements

We would like to thank A. Cerny for animal husbandry and genotyping and R. Johnstone for the anti-AIM2 antibody. V.H. is supported by a fellowship from the Deutsche Forschungsgemeinschaft (German Research Foundation; Ho2783/2-1), E.L. and K.A.F. are supported by grants from the National Institutes of Health (AI-065483 (to E.L.) and AI-067497 (to K.A.F.)).

Author Contributions V.H. conceived the research and conducted the experiments with A.A., M.C.-D., F.B. and G.H. D.R.C. performed sequence analysis. E.L. and K.A.F. oversaw the whole project.

Author information

Author notes

    • Eicke Latz
    •  & Katherine A. Fitzgerald

    These authors contributed equally to this work.

Affiliations

  1. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Veit Hornung
    • , Andrea Ablasser
    • , Marie Charrel-Dennis
    • , Franz Bauernfeind
    • , Gabor Horvath
    • , Eicke Latz
    •  & Katherine A. Fitzgerald
  2. Institute of Clinical Chemistry and Pharmacology, Universitätsklinikum Bonn 53127, Germany

    • Veit Hornung
    • , Andrea Ablasser
    •  & Franz Bauernfeind
  3. Pfizer, 620 Memorial Drive, Cambridge, Massachusetts 02139, USA

    • Daniel. R. Caffrey

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Corresponding authors

Correspondence to Veit Hornung or Katherine A. Fitzgerald.

Supplementary information

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