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

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          Abstract

          The innate immune system senses nucleic acids via germ-line encoded pattern recognition receptors. RNA is sensed via Toll-like receptor (TLR)−3, −7 and −8 or by the RNA helicases RIG-I and MDA-5 1. Little is known about sensors for cytoplasmic DNA which trigger antiviral and/or inflammatory responses 26. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-Interferon Regulatory Factor (IRF)-3 signaling axis to trigger transcriptional induction of IFN〈/® genes 2, 3. A second, less well-defined pathway leads to the activation of an ‘inflammasome’ which via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL-1β and IL-18 6, 7. Here we identify the IFI20X/IFI16 (PYHIN) family member 8, absent in melanoma 2 (AIM2), as a receptor for cytosolic DNA which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, while the PYD domain (but not that of the other PYHIN family members) associates with the adapter molecule ASC to activate both NF-κB and caspase-1. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA and the dsDNA virus, vaccinia. Collectively, these observations identify AIM2 as a novel receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.

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          Most cited references23

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          Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.

          Nucleic acid recognition upon viral infection triggers type I interferon production. Viral RNA is detected by both endosomal, TLR-dependent and cytosolic, RIG-I/MDA5-dependent pathways. TLR9 is the only known sensor of foreign DNA; it is unknown whether innate immune recognition of DNA exists in the cytosol. Here we present evidence that cytosolic DNA activates a potent type I interferon response to the invasive bacterium Listeria monocytogenes. The noninvasive Legionella pneumophila triggers an identical response through its type IV secretion system. Activation of type I interferons by cytosolic DNA is TLR independent and requires IRF3 but occurs without detectable activation of NF-kappaB and MAP kinases. Microarray analyses reveal a unique but overlapping gene-expression program activated by cytosolic DNA compared to TLR9- and RIG-I/MDA5-dependent responses. These findings define an innate immune response to DNA linked to type I interferon production.
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            Intracellular pattern recognition receptors in the host response.

            The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.
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              Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.

              Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                17 March 2009
                21 January 2009
                26 March 2009
                26 September 2009
                : 458
                : 7237
                : 514-518
                Affiliations
                [1 ]Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
                [2 ]Institute of Clinical Chemistry and Pharmacology, Universitätsklinikum Bonn, Germany
                [3 ]Pfizer, 620 Memorial Drive, Cambridge, MA 02139, USA
                Author notes
                Correspondence and requests for materials should be addressed to K.A.F, E.L or V.H.; kate.fitzgerald@ 123456umassmed.edu , eicke.latz@ 123456umassmed.edu or veit.hornung@ 123456uni-bonn.de
                [*]

                Equal contributors

                Author Contributions V.H conceived the research and conducted the experiments with A.A., M.C.D., F.B, G.H. D.R.C performed sequence analysis. E.L and K.A.F oversaw the whole project.

                Article
                nihpa103043
                10.1038/nature07725
                2726264
                19158675
                d3017e50-1be8-4df2-afb7-9b619af49a3c
                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI067497-05 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI067497-04 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI067497-03 ||AI
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