Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 323 (5917): 1057-1060

Copyright © 2009 by the American Association for the Advancement of Science

HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA

Tara L. Roberts,1,2* Adi Idris,1* Jasmyn A. Dunn,1 Greg M. Kelly,1 Carol M. Burnton,1 Samantha Hodgson,1 Lani L. Hardy,1 Valerie Garceau,1{dagger} Matthew J. Sweet,1,3 Ian L. Ross,1 David A. Hume,1{dagger} Katryn J. Stacey1,3{ddagger}

Abstract: The mammalian innate immune system is activated by foreign nucleic acids. Detection of double-stranded DNA (dsDNA) in the cytoplasm triggers characteristic antiviral responses and macrophage cell death. Cytoplasmic dsDNA rapidly activated caspase 3 and caspase 1 in bone marrow–derived macrophages. We identified the HIN-200 family member and candidate lupus susceptibility factor, p202, as a dsDNA binding protein that bound stably and rapidly to transfected DNA. Knockdown studies showed p202 to be an inhibitor of DNA-induced caspase activation. Conversely, the related pyrin domain–containing HIN-200 factor, AIM2 (p210), was required for caspase activation by cytoplasmic dsDNA. This work indicates that HIN-200 proteins can act as pattern recognition receptors mediating responses to cytoplasmic dsDNA.

1 The University of Queensland, Institute for Molecular Bioscience, QLD 4072, Australia.
2 Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia.
3 The University of Queensland, School of Chemistry and Biomolecular Science, QLD 4072, Australia.

* These authors contributed equally to this work.

{dagger} Present address: The Roslin Institute, University of Edinburgh, Roslin EH259PS, Scotland, UK.

{ddagger} To whom correspondence should be addressed. E-mail: k.stacey{at}imb.uq.edu.au

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid.
J. Conlon, D. L. Burdette, S. Sharma, N. Bhat, M. Thompson, Z. Jiang, V. A. K. Rathinam, B. Monks, T. Jin, T. S. Xiao, et al. (2013)
J. Immunol. 190, 5216-5225
   Abstract »    Full Text »    PDF »
Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly.
T. Jin, A. Perry, P. Smith, J. Jiang, and T. S. Xiao (2013)
J. Biol. Chem. 288, 13225-13235
   Abstract »    Full Text »    PDF »
Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection.
M. T. R. Gomes, P. C. Campos, F. S. Oliveira, P. P. Corsetti, K. R. Bortoluci, L. D. Cunha, D. S. Zamboni, and S. C. Oliveira (2013)
J. Immunol. 190, 3629-3638
   Abstract »    Full Text »    PDF »
Smg1 haploinsufficiency predisposes to tumor formation and inflammation.
T. L. Roberts, U. Ho, J. Luff, C. S. Lee, S. H. Apte, K. P. A. MacDonald, L. J. Raggat, A. R. Pettit, C. A. Morrow, M. J. Waters, et al. (2013)
PNAS 110, E285-E294
   Abstract »    Full Text »    PDF »
Francisella tularensis Live Vaccine Strain Folate Metabolism and Pseudouridine Synthase Gene Mutants Modulate Macrophage Caspase-1 Activation.
T. K. Ulland, A. M. Janowski, B. W. Buchan, M. Faron, S. L. Cassel, B. D. Jones, and F. S. Sutterwala (2013)
Infect. Immun. 81, 201-208
   Abstract »    Full Text »    PDF »
Extensive evolutionary and functional diversity among mammalian AIM2-like receptors.
R. L. Brunette, J. M. Young, D. G. Whitley, I. E. Brodsky, H. S. Malik, and D. B. Stetson (2012)
J. Exp. Med. 209, 1969-1983
   Abstract »    Full Text »    PDF »
Critical role of AIM2 in Mycobacterium tuberculosis infection.
H. Saiga, S. Kitada, Y. Shimada, N. Kamiyama, M. Okuyama, M. Makino, M. Yamamoto, and K. Takeda (2012)
Int. Immunol. 24, 637-644
   Abstract »    Full Text »    PDF »
Inflammasomes and viruses: cellular defence versus viral offence.
A. M. Gram, J. Frenkel, and M. E. Ressing (2012)
J. Gen. Virol. 93, 2063-2075
   Abstract »    Full Text »    PDF »
Plenary Perspective: The complexity of constitutive and inducible gene expression in mononuclear phagocytes.
D. A. Hume (2012)
J. Leukoc. Biol. 92, 433-444
   Abstract »    Full Text »    PDF »
Nicotinamide nucleotide transhydrogenase (NNT) acts as a novel modulator of macrophage inflammatory responses.
V. M. Ripoll, N. A. Meadows, M. Bangert, A. W. Lee, A. Kadioglu, and R. D. Cox (2012)
FASEB J 26, 3550-3562
   Abstract »    Full Text »    PDF »
IFN-{beta} Expression Is Directly Activated in Human Neutrophils Transfected with Plasmid DNA and Is Further Increased via TLR-4-Mediated Signaling.
N. Tamassia, F. Bazzoni, V. Le Moigne, F. Calzetti, C. Masala, G. Grisendi, U. Bussmeyer, S. Scutera, M. De Gironcoli, C. Costantini, et al. (2012)
J. Immunol. 189, 1500-1509
   Abstract »    Full Text »    PDF »
Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16.
T. Li, B. A. Diner, J. Chen, and I. M. Cristea (2012)
PNAS 109, 10558-10563
   Abstract »    Full Text »    PDF »
Subversion of Host Recognition and Defense Systems by Francisella spp..
C. L. Jones, B. A. Napier, T. R. Sampson, A. C. Llewellyn, M. R. Schroeder, and D. S. Weiss (2012)
Microbiol. Mol. Biol. Rev. 76, 383-404
   Abstract »    Full Text »    PDF »
Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking.
J. Ge, Y.-N. Gong, Y. Xu, and F. Shao (2012)
PNAS 109, 6193-6198
   Abstract »    Full Text »    PDF »
Sensing Adenovirus Infection: Activation of Interferon Regulatory Factor 3 in RAW 264.7 Cells.
S. C. Stein and E. Falck-Pedersen (2012)
J. Virol. 86, 4527-4537
   Abstract »    Full Text »    PDF »
Activation of the Pyrin Inflammasome by Intracellular Burkholderia cenocepacia.
M. A. Gavrilin, D. H. A. Abdelaziz, M. Mostafa, B. A. Abdulrahman, J. Grandhi, A. Akhter, A. Abu Khweek, D. F. Aubert, M. A. Valvano, M. D. Wewers, et al. (2012)
J. Immunol. 188, 3469-3477
   Abstract »    Full Text »    PDF »
Activation of the NLRP3 Inflammasome by Group B Streptococci.
A. Costa, R. Gupta, G. Signorino, A. Malara, F. Cardile, C. Biondo, A. Midiri, R. Galbo, P. Trieu-Cuot, S. Papasergi, et al. (2012)
J. Immunol. 188, 1953-1960
   Abstract »    Full Text »    PDF »
Caspase-4 Is Required for Activation of Inflammasomes.
G. Sollberger, G. E. Strittmatter, M. Kistowska, L. E. French, and H.-D. Beer (2012)
J. Immunol. 188, 1992-2000
   Abstract »    Full Text »    PDF »
DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.
B. J. Ferguson, D. S. Mansur, N. E. Peters, H. Ren, and G. L. Smith (2012)
eLife Sci 1, e00047
   Abstract »    Full Text »    PDF »
Cytosolic DNA Triggers Mitochondrial Apoptosis via DNA Damage Signaling Proteins Independently of AIM2 and RNA Polymerase III.
M. Wenzel, M. Wunderlich, R. Besch, H. Poeck, S. Willms, A. Schwantes, M. Kremer, G. Sutter, S. Endres, A. Schmidt, et al. (2012)
J. Immunol. 188, 394-403
   Abstract »    Full Text »    PDF »
Distinct Regulation of Murine Lupus Susceptibility Genes by the IRF5/Blimp-1 Axis.
R. Panchanathan, H. Liu, H. Liu, C.-M. Fang, L. D. Erickson, P. M. Pitha, and D. Choubey (2012)
J. Immunol. 188, 270-278
   Abstract »    Full Text »    PDF »
Measles Virus V Protein Inhibits NLRP3 Inflammasome-Mediated Interleukin-1{beta} Secretion.
N. Komune, T. Ichinohe, M. Ito, and Y. Yanagi (2011)
J. Virol. 85, 13019-13026
   Abstract »    Full Text »    PDF »
Myxoma Virus Lacking the Pyrin-Like Protein M013 Is Sensed in Human Myeloid Cells by both NLRP3 and Multiple Toll-Like Receptors, Which Independently Activate the Inflammasome and NF-{kappa}B Innate Response Pathways.
M. M. Rahman and G. McFadden (2011)
J. Virol. 85, 12505-12517
   Abstract »    Full Text »    PDF »
DHX9 Pairs with IPS-1 To Sense Double-Stranded RNA in Myeloid Dendritic Cells.
Z. Zhang, B. Yuan, N. Lu, V. Facchinetti, and Y.-J. Liu (2011)
J. Immunol. 187, 4501-4508
   Abstract »    Full Text »    PDF »
Critical Roles of ASC Inflammasomes in Caspase-1 Activation and Host Innate Resistance to Streptococcus pneumoniae Infection.
R. Fang, K. Tsuchiya, I. Kawamura, Y. Shen, H. Hara, S. Sakai, T. Yamamoto, T. Fernandes-Alnemri, R. Yang, E. Hernandez-Cuellar, et al. (2011)
J. Immunol. 187, 4890-4899
   Abstract »    Full Text »    PDF »
Cytosolic DNA-Activated Human Dendritic Cells Are Potent Activators of the Adaptive Immune Response.
K. Kis-Toth, A. Szanto, T.-H. Thai, and G. C. Tsokos (2011)
J. Immunol. 187, 1222-1234
   Abstract »    Full Text »    PDF »
Aim2 Deficiency in Mice Suppresses the Expression of the Inhibitory Fc{gamma} Receptor (Fc{gamma}RIIB) through the Induction of the IFN-Inducible p202, a Lupus Susceptibility Protein.
R. Panchanathan, H. Shen, X. Duan, V. A. K. Rathinam, L. D. Erickson, K. A. Fitzgerald, and D. Choubey (2011)
J. Immunol. 186, 6762-6770
   Abstract »    Full Text »    PDF »
The NLR Adaptor ASC/PYCARD Regulates DUSP10, Mitogen-activated Protein Kinase (MAPK), and Chemokine Induction Independent of the Inflammasome.
D. J. Taxman, E. A. Holley-Guthrie, M. T.-H. Huang, C. B. Moore, D. T. Bergstralh, I. C. Allen, Y. Lei, D. Gris, and J. P.-Y. Ting (2011)
J. Biol. Chem. 286, 19605-19616
   Abstract »    Full Text »    PDF »
The mononuclear phagocyte system of the pig as a model for understanding human innate immunity and disease.
L. Fairbairn, R. Kapetanovic, D. P. Sester, and D. A. Hume (2011)
J. Leukoc. Biol. 89, 855-871
   Abstract »    Full Text »    PDF »
The Inflammasomes in Kidney Disease.
H.-J. Anders and D. A. Muruve (2011)
J. Am. Soc. Nephrol. 22, 1007-1018
   Abstract »    Full Text »    PDF »
Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic Lesions.
Y. Dombrowski, M. Peric, S. Koglin, C. Kammerbauer, C. Goss, D. Anz, M. Simanski, R. Glaser, J. Harder, V. Hornung, et al. (2011)
Science Translational Medicine 3, 82ra38
   Abstract »    Full Text »    PDF »
Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition.
E. L. Lousberg, K. R. Diener, C. K. Fraser, S. Phipps, P. S. Foster, W. Chen, S. Uematsu, S. Akira, S. A. Robertson, M. P. Brown, et al. (2011)
J. Virol. 85, 3385-3396
   Abstract »    Full Text »    PDF »
Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity.
D. A. Hume (2011)
J. Leukoc. Biol. 89, 525-538
   Abstract »    Full Text »    PDF »
TBK1-associated Protein in Endolysosomes (TAPE) Is an Innate Immune Regulator Modulating the TLR3 and TLR4 Signaling Pathways.
C.-H. Chang, L.-C. Lai, H.-C. Cheng, K.-R. Chen, Y.-Z. Syue, H.-C. Lu, W.-Y. Lin, S.-H. Chen, H.-S. Huang, A.-L. Shiau, et al. (2011)
J. Biol. Chem. 286, 7043-7051
   Abstract »    Full Text »    PDF »
NLRC5 Deficiency Does Not Influence Cytokine Induction by Virus and Bacteria Infections.
H. Kumar, S. Pandey, J. Zou, Y. Kumagai, K. Takahashi, S. Akira, and T. Kawai (2011)
J. Immunol. 186, 994-1000
   Abstract »    Full Text »    PDF »
Aim2 Deficiency Stimulates the Expression of IFN-Inducible Ifi202, a Lupus Susceptibility Murine Gene within the Nba2 Autoimmune Susceptibility Locus.
R. Panchanathan, X. Duan, H. Shen, V. A. K. Rathinam, L. D. Erickson, K. A. Fitzgerald, and D. Choubey (2010)
J. Immunol. 185, 7385-7393
   Abstract »    Full Text »    PDF »
Deletion of ripA Alleviates Suppression of the Inflammasome and MAPK by Francisella tularensis.
M. T.-H. Huang, B. L. Mortensen, D. J. Taxman, R. R. Craven, S. Taft-Benz, T. M. Kijek, J. R. Fuller, B. K. Davis, I. C. Allen, W. J. Brickey, et al. (2010)
J. Immunol. 185, 5476-5485
   Abstract »    Full Text »    PDF »
Inhibition of the RNA polymerase III-mediated dsDNA-sensing pathway of innate immunity by vaccinia virus protein E3.
R. Valentine and G. L. Smith (2010)
J. Gen. Virol. 91, 2221-2229
   Abstract »    Full Text »    PDF »
Cutting Edge: Mutation of Francisella tularensis mviN Leads to Increased Macrophage Absent in Melanoma 2 Inflammasome Activation and a Loss of Virulence.
T. K. Ulland, B. W. Buchan, M. R. Ketterer, T. Fernandes-Alnemri, D. K. Meyerholz, M. A. Apicella, E. S. Alnemri, B. D. Jones, W. M. Nauseef, and F. S. Sutterwala (2010)
J. Immunol. 185, 2670-2674
   Abstract »    Full Text »    PDF »
Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein.
I. M. Cristea, N. J. Moorman, S. S. Terhune, C. D. Cuevas, E. S. O'Keefe, M. P. Rout, B. T. Chait, and T. Shenk (2010)
J. Virol. 84, 7803-7814
   Abstract »    Full Text »    PDF »
Cutting Edge: Cytosolic Bacterial DNA Activates the Inflammasome via Aim2.
S. E. Warren, A. Armstrong, M. K. Hamilton, D. P. Mao, I. A. Leaf, E. A. Miao, and A. Aderem (2010)
J. Immunol. 185, 818-821
   Abstract »    Full Text »    PDF »
Involvement of Absent in Melanoma 2 in Inflammasome Activation in Macrophages Infected with Listeria monocytogenes.
K. Tsuchiya, H. Hara, I. Kawamura, T. Nomura, T. Yamamoto, S. Daim, S. R. Dewamitta, Y. Shen, R. Fang, and M. Mitsuyama (2010)
J. Immunol. 185, 1186-1195
   Abstract »    Full Text »    PDF »
Innate Immune Recognition in Infectious and Noninfectious Diseases of the Lung.
B. Opitz, V. van Laak, J. Eitel, and N. Suttorp (2010)
181, 1294-1309
   Abstract »    Full Text »    PDF »
(1,3)-{beta}-Glucans Activate Both Dectin-1 and NLRP3 Inflammasome in Human Macrophages.
P. Kankkunen, L. Teirila, J. Rintahaka, H. Alenius, H. Wolff, and S. Matikainen (2010)
J. Immunol. 184, 6335-6342
   Abstract »    Full Text »    PDF »
Inflammatory Stimuli Regulate Caspase Substrate Profiles.
N. J. Agard, D. Maltby, and J. A. Wells (2010)
Mol. Cell. Proteomics 9, 880-893
   Abstract »    Full Text »    PDF »
Comment on "Development of Murine Lupus Involves the Combined Genetic Contribution of the SLAM and Fc{gamma}R Intervals within the Nba2 Autoimmune Susceptibility Locus".
D. Choubey, R. Panchanathan, H. Shen, and X. Duan (2010)
J. Immunol. 184, 4051-4052
   Full Text »    PDF »
A visual framework for sequence analysis using n-grams and spectral rearrangement.
S. R. Maetschke, K. S. Kassahn, J. A. Dunn, S.-P. Han, E. Z. Curley, K. J. Stacey, and M. A. Ragan (2010)
Bioinformatics 26, 737-744
   Abstract »    Full Text »    PDF »
Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-{beta} Production.
J. N. Gabhann, R. Higgs, K. Brennan, W. Thomas, J. E. Damen, N. Ben Larbi, G. Krystal, and C. A. Jefferies (2010)
J. Immunol. 184, 2314-2320
   Abstract »    Full Text »    PDF »
TLR9 Regulates TLR7- and MyD88-Dependent Autoantibody Production and Disease in a Murine Model of Lupus.
K. M. Nickerson, S. R. Christensen, J. Shupe, M. Kashgarian, D. Kim, K. Elkon, and M. J. Shlomchik (2010)
J. Immunol. 184, 1840-1848
   Abstract »    Full Text »    PDF »
Extrachromosomal Histone H2B Mediates Innate Antiviral Immune Responses Induced by Intracellular Double-Stranded DNA.
K. Kobiyama, F. Takeshita, N. Jounai, A. Sakaue-Sawano, A. Miyawaki, K. J. Ishii, T. Kawai, S. Sasaki, H. Hirano, N. Ishii, et al. (2010)
J. Virol. 84, 822-832
   Abstract »    Full Text »    PDF »
Listeria monocytogenes-Infected Human Peripheral Blood Mononuclear Cells Produce IL-1{beta}, Depending on Listeriolysin O and NLRP3.
K. Meixenberger, F. Pache, J. Eitel, B. Schmeck, S. Hippenstiel, H. Slevogt, P. N'Guessan, M. Witzenrath, M. G. Netea, T. Chakraborty, et al. (2010)
J. Immunol. 184, 922-930
   Abstract »    Full Text »    PDF »
Female and Male Sex Hormones Differentially Regulate Expression of Ifi202, an Interferon-Inducible Lupus Susceptibility Gene within the Nba2 Interval.
R. Panchanathan, H. Shen, M. G. Bupp, K. A. Gould, and D. Choubey (2009)
J. Immunol. 183, 7031-7038
   Abstract »    Full Text »    PDF »
Interferons Direct an Effective Innate Response to Legionella pneumophila Infection.
C. R. Plumlee, C. Lee, A. A. Beg, T. Decker, H. A. Shuman, and C. Schindler (2009)
J. Biol. Chem. 284, 30058-30066
   Abstract »    Full Text »    PDF »
Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.
Y. J. Crow and J. Rehwinkel (2009)
Hum. Mol. Genet. 18, R130-R136
   Abstract »    Full Text »    PDF »
Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR.
I Kimkong, Y Avihingsanon, and N Hirankarn (2009)
Lupus 18, 1066-1072
   Abstract »    PDF »
Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation.
R. Kenworthy, D. Lambert, F. Yang, N. Wang, Z. Chen, H. Zhu, F. Zhu, C. Liu, K. Li, and H. Tang (2009)
Nucleic Acids Res. 37, 6587-6599
   Abstract »    Full Text »    PDF »
Requirement for DNA CpG Content in TLR9-Dependent Dendritic Cell Activation Induced by DNA-Containing Immune Complexes.
K. Yasuda, C. Richez, M. B. Uccellini, R. J. Richards, R. G. Bonegio, S. Akira, M. Monestier, R. B. Corley, G. A. Viglianti, A. Marshak-Rothstein, et al. (2009)
J. Immunol. 183, 3109-3117
   Abstract »    Full Text »    PDF »
Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice.
S. Bolland and A. Garcia-Sastre (2009)
J. Exp. Med. 206, 1647-1651
   Abstract »    Full Text »    PDF »
Caspase-8 for Outer Harmony.
G. Sollberger and H.-D. Beer (2009)
Science Signaling 2, pe40
   Abstract »    Full Text »    PDF »
AIMing 2 Detect Foreign DNA.
A. M. Krieg (2009)
Science Signaling 2, pe39
   Abstract »    Full Text »    PDF »
Pyrin Critical to Macrophage IL-1{beta} Response to Francisella Challenge.
M. A. Gavrilin, S. Mitra, S. Seshadri, J. Nateri, F. Berhe, M. W. Hall, and M. D. Wewers (2009)
J. Immunol. 182, 7982-7989
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882