An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome
Abstract
Cytoplasmic DNA triggers activation of the innate immune system. Although 'downstream' signaling components have been characterized, the DNA-sensing components remain elusive. Here we present a systematic proteomics screen for proteins that associate with DNA, 'crossed' to a screen for transcripts induced by interferon-beta, which identified AIM2 as a candidate cytoplasmic DNA sensor. AIM2 showed specificity for double-stranded DNA. It also recruited the inflammasome adaptor ASC and localized to ASC 'speckles'. A decrease in AIM2 expression produced by RNA-mediated interference impaired DNA-induced maturation of interleukin 1beta in THP-1 human monocytic cells, which indicated that endogenous AIM2 is required for DNA recognition. Reconstitution of unresponsive HEK293 cells with AIM2, ASC, caspase-1 and interleukin 1beta showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [48]
Cites
Summaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,906 · see citing works
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., & Latz, E. (2008) · Nature Immunology · doi:10.1038/ni.1631 · Cited by 3,065 · see citing works
Baechler, E. C., Batliwalla, F., Karypis, G., Gaffney, P. M., Ortmann, W. A., Espe, K. J., Shark, K. B., Grande, W. J., Hughes, K. M. H., Kapur, V., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0337679100 · Cited by 2,246 · see citing works
DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
Takaoka, A., Wang, Z., Choi, M. K., Yanai, H., Negishi, H., Ban, T., Lu, Y., Miyagishi, M., Kodama, T., Honda, K., et al. (2007) · Nature · doi:10.1038/nature06013 · Cited by 1,704 · see citing works
Trex1 prevents cell-intrinsic initiation of autoimmunity
Stetson, D. B., Ko, J. S., Heidmann, T., & Medzhitov, R. (2008) · Cell · doi:10.1016/j.cell.2008.06.032 · Cited by 1,280 · see citing works
Intracellular NOD-like Receptors in Host Defense and Disease
Kanneganti, T., Lamkanfi, M., & Núñez, G. (2007) · Immunity · doi:10.1016/j.immuni.2007.10.002 · Cited by 1,056 · see citing works
Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response
Stetson, D. B., & Medzhitov, R. M. (2006) · Immunity · doi:10.1016/j.immuni.2005.12.003 · Cited by 1,003 · see citing works
The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response
Muruve, D. A., Pétrilli, V., Zaiss, A. K., White, L. R., Clark, S. A., Ross, P. J., Parks, R. J., & Tschopp, J. (2008) · Nature · doi:10.1038/nature06664 · Cited by 936 · see citing works
A Toll-like receptor–independent antiviral response induced by double-stranded B-form DNA
Ishii, K. J., Coban, C., Kato, H., Takahashi, K., Torii, Y., Takeshita, F., Ludwig, H., Sutter, G., Suzuki, K., Hemmi, H., et al. (2005) · Nature Immunology · doi:10.1038/ni1282 · Cited by 771 · see citing works
The inflammasome: a danger sensing complex triggering innate immunity
Pétrilli, V., Dostert, C., Muruve, D. A., & Tschopp, J. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.09.002 · Cited by 700 · see citing works
Pichlmair, A., & Sousa, C. R. E. (2007) · Immunity · doi:10.1016/j.immuni.2007.08.012 · Cited by 690 · see citing works
TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
Ishii, K. J., Kawagoe, T., Koyama, S., Matsui, K., Kumar, H., Kawai, T., Uematsu, S., Takeuchi, O., Takeshita, F., Coban, C., et al. (2008) · Nature · doi:10.1038/nature06537 · Cited by 628 · see citing works
An efficient tandem affinity purification procedure for interaction proteomics in mammalian cells
Bürckstümmer, T., Bennett, K. L., Preradovic, A., Schütze, G. A., Hantschel, O. D., Superti‐Furga, G., & Bauch, A. (2006) · Nature Methods · doi:10.1038/nmeth968 · Cited by 391 · see citing works
Self-citationMorita, M., Stamp, G., Robins, P., Dulic, A., Rosewell, I. R., Hrivnak, G., Daly, G., Lindahl, T. L., & Barnes, D. E. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.15.6719-6727.2004 · Cited by 380 · see citing works
Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules
Wang, Z., Choi, M. K., Ban, T., Yanai, H., Negishi, H., Lu, Y., Tamura, T., Takaoka, A., Nishikura, K., & Taniguchi, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801295105 · Cited by 337 · see citing works
Johnston, J. B., Barrett, J. W., Nazarian, S. H., Goodwin, M., Ricuttio, D., Wang, G., & McFadden, G. (2005) · Immunity · doi:10.1016/j.immuni.2005.10.003 · Cited by 231 · see citing works
The Caspase-1 Inflammasome: A Pilot of Innate Immune Responses
Yu, H. B., & Finlay, B. B. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.08.007 · Cited by 223 · see citing works
Excision of 3′ Termini by the Trex1 and TREX2 3′→5′ Exonucleases
Mazur, D. J., & Perrino, F. W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100623200 · Cited by 147 · see citing works
Interferon-inducible Ifi200-family genes in systemic lupus erythematosus
Choubey, D., & Panchanathan, R. (2008) · Immunology Letters · doi:10.1016/j.imlet.2008.06.001 · Cited by 109 · see citing works
Pyrin N-Terminal Homology Domain- and Caspase Recruitment Domain-Dependent Oligomerization of ASC
Masumoto, J., Taniguchi, S., & Sagara, J. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.4190 · Cited by 88 · see citing works
Woerner, S. M., Kloor, M., Schwitalle, Y., Youmans, H., Doeberitz, M. V. K., Gebert, J. F., & Dihlmann, S. (2007) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20493 · Cited by 86 · see citing works
A Shope Fibroma virus PYRIN-only protein modulates the host immune response
Dorfleutner, A., Talbott, S. J., Bryan, N. B., Funya, K. N., Rellick, S. L., Reed, J. C., Shi, X., Rojanasakul, Y., Flynn, D. C., & Stehlik, C. (2007) · Virus Genes · doi:10.1007/s11262-007-0141-9 · Cited by 85 · see citing works
The HIN domain of IFI-200 proteins consists of two OB folds
Albrecht, M., Choubey, D., & Lengauer, T. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.12.056 · Cited by 85 · see citing works
Caposio, P., Gugliesi, F., Zannetti, C., Sponza, S., Mondini, M., Médico, E., Hiscott, J. B., Young, H. A., Gribaudo, G., Gariglio, M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701846200 · Cited by 68 · see citing works
Role of Charged and Hydrophobic Residues in the Oligomerization of the PYRIN Domain of ASC
Moriya, M., Taniguchi, S., Wu, P., et al. (2004) · Biochemistry · doi:10.1021/bi048374i · Cited by 61 · see citing works
Structure and Dynamics of ASC2, a Pyrin Domain-only Protein That Regulates Inflammatory Signaling
Natarajan, A., Ghose, R., & Hill, J. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605458200 · Cited by 48 · see citing works
Synthesis and nuclease susceptibility of alpha-oligodeoxyribonucleotide phosphorothioate.
Shinozuka, K., Morita, T., & Sawai, H. (1991) · PubMed · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Schroder, K., & Tschopp, J. (2010) · Cell · doi:10.1016/j.cell.2010.01.040 · Cited by 5,475 · see citing works
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051 · see citing works
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Coll, R. C., Robertson, A. A. B., Chae, J. J., Higgins, S. C., Muñoz-Planillo, R., Inserra, M. C., Vetter, I., Dungan, L. S., Monks, B. G., Stutz, A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3806 · Cited by 2,849 · see citing works
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Ishikawa, H., Ma, Z., & Barber, G. N. (2009) · Nature · doi:10.1038/nature08476 · Cited by 2,759 · see citing works
Franchi, L., Eigenbrod, T., Muñoz-Planillo, R., & Nuñez, G. (2009) · Nature Immunology · doi:10.1038/ni.1703 · Cited by 1,834 · see citing works
IFI16 is an innate immune sensor for intracellular DNA
Unterholzner, L., Keating, S. E., Baran, M., Horan, K. A., Jensen, S. B., Sharma, S., Sirois, C. M., Jin, T., Latz, E., Xiao, T. S., et al. (2010) · Nature Immunology · doi:10.1038/ni.1932 · Cited by 1,643 · see citing works
DNA sensing by the cGAS–STING pathway in health and disease
Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0151-1 · Cited by 1,467 · see citing works
Understanding the mechanism of IL-1β secretion
Lopez-Castejon, G., & Brough, D. (2011) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2011.10.001 · Cited by 1,519 · see citing works
Shi, C.-S., Shenderov, K., Huang, N.-N., Kabat, J., Abu-Asab, M., Fitzgerald, K. A., Sher, A., & Kehrl, J. H. (2012) · Nature Immunology · doi:10.1038/ni.2215 · Cited by 1,367 · see citing works
The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses
Rathinam, V. A. K., Jiang, Z., Waggoner, S. N., Sharma, S., Cole, L. E., Waggoner, L., Vanaja, S. K., Monks, B. G., Ganesan, S., Latz, E., et al. (2010) · Nature Immunology · doi:10.1038/ni.1864 · Cited by 1,331 · see citing works
Gao, P., Ascano, M., Wu, Y., Barchet, W., Gaffney, B. L., Zillinger, T., Serganov, A. A., Liu, Y., Jones, R. A., Hartmann, G., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.046 · Cited by 1,101 · see citing works
Pyroptotic cell death defends against intracellular pathogens
Jorgensen, I., & Miao, E. A. (2015) · Immunological Reviews · doi:10.1111/imr.12287 · Cited by 1,021 · see citing works
The Sterile Inflammatory Response
Rock, K. L., Latz, E., Ontiveros, F., & Kono, H. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101311 · Cited by 865 · see citing works
Allen, I. C., TeKippe, E. M., Woodford, R.-M. T., Uronis, J. M., Holl, E. K., Rogers, A. B., Herfarth, H. H., Jobin, C., & Ting, J. P.-Y. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100050 · Cited by 826 · see citing works
The inflammasome: an integrated view
Gross, O., Thomas, C. J., Guarda, G., & Tschopp, J. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01046.x · Cited by 778 · see citing works
Mechanism of NLRP3 inflammasome activation
Sutterwala, F. S., Haasken, S., & Cassel, S. L. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12458 · Cited by 736 · see citing works
The AIM2 inflammasome is critical for innate immunity to Francisella tularensis
Fernandes-Alnemri, T., Yu, J.-W., Juliana, C., Solorzano, L., Kang, S., Wu, J., Datta, P., McCormick, M., Huang, L., McDermott, E., et al. (2010) · Nature Immunology · doi:10.1038/ni.1859 · Cited by 732 · see citing works
Kerur, N., Veettil, M. V., Sharma-Walia, N., Bottero, V., Sadagopan, S., Otageri, P., & Chandran, B. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.04.008 · Cited by 702 · see citing works
Bauernfeind, F., Bartok, E., Rieger, A., Franchi, L., Núñez, G., & Hornung, V. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100613 · Cited by 617 · see citing works
Nucleic acid recognition by the innate immune system
Barbalat, R., Ewald, S. E., Mouchess, M. L., & Barton, G. M. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101340 · Cited by 577 · see citing works
Samir, P., Malireddi, R. K. S., & Kanneganti, T.-D. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00238 · Cited by 557 · see citing works
IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV
Monroe, K. M., Yang, Z., Johnson, J. R., Geng, X., Doitsh, G., Krogan, N. J., & Greene, W. C. (2014) · Science · doi:10.1126/science.1243640 · Cited by 511 · see citing works
DNA Repair Pathway Choices in CRISPR-Cas9-Mediated Genome Editing
Xue, C., & Greene, E. C. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.02.008 · Cited by 431 · see citing works
Electroporation delivery of DNA vaccines: prospects for success
Sardesai, N. Y., & Weiner, D. B. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.03.008 · Cited by 416 · see citing works
NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes
Freeman, L., Guo, H., David, C. N., Brickey, W. J., Jha, S., & Ting, J. P.-Y. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20150237 · Cited by 397 · see citing works
Man, S. M., Karki, R., Malireddi, R. K. S., Neale, G., Vogel, P., Yamamoto, M., Lamkanfi, M., & Kanneganti, T.-D. (2015) · Nature Immunology · doi:10.1038/ni.3118 · Cited by 380 · see citing works
Man, S. M., Karki, R., & Kanneganti, T. (2016) · European Journal of Immunology · doi:10.1002/eji.201545839 · Cited by 354 · see citing works
The <scp>AIM</scp>2 inflammasome: Sensor of pathogens and cellular perturbations
Lugrin, J., & Martinon, F. (2018) · Immunological Reviews · doi:10.1111/imr.12618 · Cited by 333 · see citing works
Taru, V., Szabo, G., Mehal, W., & Reiberger, T. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.06.016 · Cited by 344 · see citing works
IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes
Man, S. M., Karki, R., Sasai, M., Place, D. E., Kesavardhana, S., Temirov, J., Frase, S., Zhu, Q., Malireddi, R. K. S., Kuriakose, T., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.012 · Cited by 312 · see citing works
Li, T., Diner, B. A., Chen, J., & Cristea, I. M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203447109 · Cited by 297 · see citing works
Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection
Aachoui, Y., Sagulenko, V., Miao, E. A., & Stacey, K. J. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.04.004 · Cited by 296 · see citing works
Beckwith, K. S., Beckwith, M. S., Ullmann, S., Sætra, R. S., Kim, H., Marstad, A., Åsberg, S. E., Strand, T. A., Haug, M., Niederweis, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16143-6 · Cited by 282 · see citing works
Sensing damage by the NLRP3 inflammasome
Leemans, J. C., Cassel, S. L., & Sutterwala, F. S. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01043.x · Cited by 281 · see citing works
Johnson, K. E., Chikoti, L., & Chandran, B. (2013) · Journal of Virology · doi:10.1128/jvi.00082-13 · Cited by 271 · see citing works
Cytosolic DNA Sensing in Organismal Tumor Control
Vanpouille-Box, C., Demaria, S., Formenti, S. C., & Galluzzi, L. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.013 · Cited by 250 · see citing works
Cristea, I. M., Moorman, N. J., Terhune, S. S., Cuevas, C. D., O'Keefe, E. S., Rout, M. P., Chait, B. T., & Shenk, T. (2010) · Journal of Virology · doi:10.1128/jvi.00139-10 · Cited by 155 · see citing works
AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity
Di Micco, A., Frera, G., Lugrin, J., Jamilloux, Y., Hsu, E.-T., Tardivel, A., De Gassart, A., Zaffalon, L., Bujisic, B., Siegert, S., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602419113 · Cited by 143 · see citing works
Functional Dissection of the TBK1 Molecular Network
Goncalves, A., Bürckstümmer, T., Dixit, E., Scheicher, R., Górna, M. W., Karayel, E., Sugar, C., Stukalov, A., Berg, T., Kralovics, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023971 · Cited by 136 · see citing works
Self-citationYasuda, K., Richez, C., Uccellini, M. B., Richards, R. J., Bonegio, R. G., Akira, S., Monestier, M., Corley, R. B., Viglianti, G. A., Marshak-Rothstein, A., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900399 · Cited by 118 · see citing works
Kaminski, J. J., Schattgen, S. A., Tzeng, T.-C., Bode, C., Klinman, D. M., & Fitzgerald, K. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300530 · Cited by 112 · see citing works
RNA Mediated toll-like receptor stimulation in health and disease
Dalpke, A. H., & Helm, M. (2012) · RNA Biology · doi:10.4161/rna.20206 · Cited by 113 · see citing works
Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity
Zahid, A., Ismail, H., Li, B., & Jin, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613039 · Cited by 100 · see citing works
Mycobacterium tuberculosis and the host cell inflammasome: a complex relationship
Briken, V., Ahlbrand, S. E., & Shah, S. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00062 · Cited by 92 · see citing works
Hyaluronan digestion controls DC migration from the skin
Muto, J., Morioka, Y., Yamasaki, K., Kim, M., Garcia, A., Carlin, A. F., Varki, A., & Gallo, R. L. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67947 · Cited by 84 · see citing works
Gabhann, J. N., Higgs, R., Brennan, K., Thomas, W., Damen, J. E., Ben Larbi, N., Krystal, G., & Jefferies, C. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902589 · Cited by 81 · see citing works
Maturation-dependent expression of AIM2 in human B-cells
Svensson, A., Patzi Churqui, M., Schlüter, K., Lind, L., & Eriksson, K. (2017) · PLOS ONE · doi:10.1371/journal.pone.0183268 · Cited by 32 · see citing works
- Authors
- Bürckstümmer, T., Baumann, C., Blüml, S., Dixit, E., Dürnberger, G., Jahn, H., Planyavsky, M., Bilban, M., Colinge, J., Bennett, K. L., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- Medical University of Vienna (AT)
- ORCID
- Venue
- Nature Immunology
- Published
- 2009-01-21
- Volume
- 10
- Issue
- 3
- Pages
- 266-272
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2072118838
- Cited by
- 1,091
- References
- 27
- Citations by year
- 2026: 28 · 2025: 33 · 2024: 51 · 2023: 48 · 2022: 47 · 2021: 44 · 2020: 55 · 2019: 55 · 2018: 56 · 2017: 61 · 2016: 55 · 2015: 64 · 2014: 67 · 2013: 85 · 2012: 78
- FWCI
- 45.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- 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, inflammasome, innate immunity, ASC, caspase-1, THP-1 cells
- MeSH terms
- Animals, Cytosol, DNA, DNA-Binding Proteins, Humans, Immunity, Innate, Nuclear Proteins, Interferon-beta, Caspase 1, Gene Expression Profiling, Genomics, Proteomics, NIH 3T3 Cells, Adaptor Proteins, Signal Transducing, Mice, Interleukin-1beta
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review