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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Emad S. Alnemri.

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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)

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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). https://doi.org/10.1038/nature07710

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