Letter | Published:

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

Nature volume 458, pages 514518 (26 March 2009) | Download Citation



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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  1. 1.

    , & Intracellular pattern recognition receptors in the host response. Nature 442, 39–44 (2006)

  2. 2.

    et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40–48 (2006)

  3. 3.

    & Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006)

  4. 4.

    et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007)

  5. 5.

    et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008)

  6. 6.

    et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008)

  7. 7.

    et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008)

  8. 8.

    , & The HIN-200 family: more than interferon-inducible genes? Exp. Cell Res. 308, 1–17 (2005)

  9. 9.

    & Innate immune recognition of, and regulation by, DNA. Trends Immunol. 27, 525–532 (2006)

  10. 10.

    et al. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-κB. J. Biol. Chem. 277, 11570–11575 (2002)

  11. 11.

    et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-κB and caspase-1. FEBS Lett. 530, 73–78 (2002)

  12. 12.

    et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J. Biol. Chem. 277, 29874–29880 (2002)

  13. 13.

    , & Identifying protein domains with the Pfam database. Curr. Protoc. Bioinformatics Chapter 2, Unit–2.5 (2003)

  14. 14.

    , & The HIN domain of IFI-200 proteins consists of two OB folds. Biochem. Biophys. Res. Commun. 327, 679–687 (2005)

  15. 15.

    , , & The Ifi 200 genes: an emerging family of IFN-inducible genes. Biochimie 80, 721–728 (1998)

  16. 16.

    et al. Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer. Oncogene 23, 4556–4566 (2004)

  17. 17.

    et al. A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-γ in myeloid cells. Immunogenetics 36, 369–376 (1992)

  18. 18.

    , & Characterization of the human myeloid cell nuclear differentiation antigen: relationship to interferon-inducible proteins. J. Cell. Biochem. 48, 190–202 (1992)

  19. 19.

    et al. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15, 453–457 (1997)

  20. 20.

    et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ. 13, 236–249 (2006)

  21. 21.

    et al. Computer program for determining fluorescence resonance energy transfer efficiency from flow cytometric data on a cell-by-cell basis. Comput. Methods Programs Biomed. 75, 201–211 (2004)

  22. 22.

    et al. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 204, 987–994 (2007)

  23. 23.

    , , & Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1β, IL-6, IL-8, IL-10 and TNF-α from normal human mononuclear cells involving in the lupus pathogenesis. Immunology 99, 352–360 (2000)

  24. 24.

    et al. Enzymatic synthesis of deoxyribonucleic acid. VII. Synthesis of a polymer of deoxyadenylate and deoxythymidylate. J. Biol. Chem. 235, 3242–3249 (1960)

  25. 25.

    et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568 (2006)

  26. 26.

    , & Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. J. Biol. Chem. 281, 26188–26195 (2006)

  27. 27.

    MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004)

  28. 28.

    et al. PFAAT version 2.0: a tool for editing, annotating, and analyzing multiple sequence alignments. BMC Bioinformatics 8, 381 (2007)

  29. 29.

    et al. Biochemical and growth regulatory activities of the HIN-200 family member and putative tumor suppressor protein, AIM2. Biochem. Biophys. Res. Commun. 326, 417–424 (2005)

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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.


  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.

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