Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA


Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome1, which activates caspase-1 leading to maturation of pro-interleukin-1β and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain2,3, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome4, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Activation of caspase-1 by AIM2.
Figure 2: AIM2 interacts with ASC to activate caspase-1.
Figure 3: Cell-based reconstitution of the AIM2 inflammasome.
Figure 4: In vitro reconstitution of the AIM2 inflammasome.
Figure 5: Cytoplasmic DNA-induced AIM2 oligomerization and pyroptosis.


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

    ADS  CAS  Article  Google Scholar 

  2. Choubey, D. & Panchanathan, R. Interferon-inducible Ifi200-family genes in systemic lupus erythematosus. Immunol. Lett. 119, 32–41 (2008)

    CAS  Article  Google Scholar 

  3. Ludlow, L. E., Johnstone, R. W. & Clarke, C. J. The HIN-200 family: more than interferon-inducible genes? Exp. Cell Res. 308, 1–17 (2005)

    CAS  Article  Google Scholar 

  4. Fernandes-Alnemri, T. et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 14, 1590–1604 (2007)

    CAS  Article  Google Scholar 

  5. Petrilli, V., Dostert, C., Muruve, D. A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007)

    CAS  Article  Google Scholar 

  6. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nature Immunol. 9, 857–865 (2008)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  8. Yu, J. W. et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol. Cell 28, 214–227 (2007)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20, 319–325 (2004)

    CAS  Article  Google Scholar 

  11. Albrecht, M., Choubey, D. & Lengauer, T. The HIN domain of IFI-200 proteins consists of two OB folds. Biochem. Biophys. Res. Commun. 327, 679–687 (2005)

    CAS  Article  Google Scholar 

  12. DeYoung, K. L. 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)

    CAS  Article  Google Scholar 

  13. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008)

    ADS  CAS  Article  Google Scholar 

  14. Eisenbarth, S. C., Colegio, O. R., O’Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008)

    ADS  CAS  Article  Google Scholar 

  15. Franchi, L. & Nunez, G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085–2089 (2008)

    CAS  Article  Google Scholar 

  16. Meier, O., Gastaldelli, M., Boucke, K., Hemmi, S. & Greber, U. F. Early steps of clathrin-mediated endocytosis involved in phagosomal escape of Fcγ receptor-targeted adenovirus. J. Virol. 79, 2604–2613 (2005)

    CAS  Article  Google Scholar 

  17. Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002)

    CAS  Article  Google Scholar 

  18. Fernandes-Alnemri, T. & Alnemri, E. S. Chapter thirteen assembly, purification, and assay of the activity of the ASC pyroptosome. Methods Enzymol. 442, 251–270 (2008)

    CAS  Article  Google Scholar 

Download references


This work was supported by NIH grants AG14357 and AR055398 to E.S.A. We thank M. McCormick and D. Wang for technical assistance, X. Jiao for help with the confocal microscopy, J. Sagara for the anti-human ASC antibody, J. Yuan for the anti-mouse caspase-1 antibody, R. Johnstone for the anti-human AIM2 antibody, M.-C. Hung for the anti-human IFIX antibody, T. Ouchi for the IFI16 complementary DNA and E. Latz for the immortalized mouse bone marrow macrophages.

Author Contributions T.F.-A. and J.-W.Y. performed most of the experiments. J.W. and P.D. performed additional experiments and provided technical assistance with equal contribution. E.S.A. conceived and designed the experiments, analysed and interpreted the data (with T.F.-A. and J.-W.Y.), and directed the whole project.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Emad S. Alnemri.

Supplementary information

Supplementary Information

This file contains Supplementary Notes, Supplementary Figures 1-15 with Legends, Legend for Supplementary Movie 1, a Supplementary Discussion and Supplementary References (PDF 3137 kb)

Supplementary Movie 1

Supplementary Movie 1 is a. time-lapse live cell movie of cytoplasmic DNA-induced AIM2 oligomerization and pyroptosis in Nalp3-/- bone marrow macrophages. (see nature 07710-s1 for full Legend) (AVI 939 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fernandes-Alnemri, T., Yu, JW., Datta, P. et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing