Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR et al.. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458: 514-518

Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nature (Impact Factor: 41.46). 02/2009; 458(7237):514-8. DOI: 10.1038/nature07725
Source: PubMed


The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.

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Available from: Eicke Latz, Mar 15, 2014
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    • "ted with VACV or SEV ( I ) . Analyses of luciferase activity or IRF3 dimerization were performed as in ( D ) – ( F ). * * p < 0 . 01 and * * * p < 0 . 001 ; Student ' s t test . See also Figures S1 and S2 . mediated by another cytosolic DNA sensor , AIM2 ( Figures S3A and S3B ) ( Bü rckstü mmer et al . , 2009 ; Fernandes - Alnemri et al . , 2009 ; Hornung et al . , 2009 ) . The specific inhibition of cGAS by ORF52 prompted us to investigate the possibility of an interaction between the two proteins . Indeed , we found that GST - ORF52 pulled down Flag - tagged hcGAS efficiently , but not Flag - AIM2 under the same conditions ( Figure 4A ) . The inter - action between ORF52 and cGAS was evidently not de"
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    ABSTRACT: Invading viral DNA can be recognized by the host cytosolic DNA sensor, cyclic GMP-AMP (cGAMP) synthase (cGAS), resulting in production of the second messenger cGAMP, which directs the adaptor protein STING to stimulate production of type I interferons (IFNs). Although several DNA viruses are sensed by cGAS, viral strategies targeting cGAS are virtually unknown. We report here that Kaposi's sarcoma-associated herpesvirus (KSHV) ORF52, an abundant gammaherpesvirus-specific tegument protein, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity through a mechanism involving both cGAS binding and DNA binding. Moreover, ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA, suggesting conserved inhibitory mechanisms. Furthermore, KSHV infection evokes cGAS-dependent responses that can limit the infection, and an ORF52 null mutant exhibits increased cGAS signaling. Our findings reveal a mechanism through which gammaherpesviruses antagonize host cGAS DNA sensing. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 08/2015; 18(3). DOI:10.1016/j.chom.2015.07.015 · 12.33 Impact Factor
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    • "Mtb also elicits inflammatory responses, an event that is not mediated by cGAS or STING but by the intracellular inflammasome complex. Interestingly, the inflammasome-mediated host response also relies on the presence of cytosolic DNA, which is sensed by AIM2 (Saiga et al., 2012; Hornung et al., 2009). "
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    ABSTRACT: Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 06/2015; 17(6). DOI:10.1016/j.chom.2015.05.003 · 12.33 Impact Factor
    • "Of these, AIM2, p204 (also known as Ifi204) and IFI16 have been shown to bind DNA directly via their HIN domains culminating in the production of antiviral and proinflammatory cytokines. Moreover, some members of the PYHIN family (e.g., AIM2 and IFI16) can form inflammasome complexes, resulting in interleukin-1b (IL-1b) processing by caspase-1 (Burckstummer et al., 2009; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Roberts et al., 2009). In the case of IFI16, this occurs following recognition of Kaposi's sarcomaassociated herpesvirus (KSHV) genomic DNA in the cell nucleus (Kerur et al., 2011). "
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    ABSTRACT: The detection of nucleic acids by the innate immune system is an essential host response during viral infection. In recent years, a number of immune sensors capable of recognizing cytosolic DNA have been identified and include the PYHIN family members AIM2, IFI16, and p204 as well as the enzyme, cGAS. Activation of these receptors leads to the induction of antiviral genes including Type-1 interferons and chemokines such as CCL5. We have carried out extensive expression profiling of these DNA sensors and other members of the PYHIN family in highly purified primary astrocytes and microglia and have demonstrated that both cell types express the majority of these proteins at the mRNA level. In microglia, several family members are highly upregulated in response to IFN-β treatment while both cell types induce robust proinflammatory and antiviral cytokine production (e.g., IL-6, CCL5, IFN-β) in the presence of immune stimulatory DNA and RNA. The production of IL-6 is partially dependent on the interferon receptor as is IFN-β itself. Furthermore, we have found that p204 and AIM2 are upregulated in a Type I IFN dependent fashion in vivo, in a murine model of chronic neurodegeneration. Given the propensity of inflammatory responses to cause neuronal damage, increased expression and activation of these receptors, not only during viral infection but also during sterile inflammatory responses, has the potential to exacerbate existing neuroinflammation leading to further damage and impaired neurogenesis. GLIA 2015
    Glia 01/2015; 63(5). DOI:10.1002/glia.22786 · 6.03 Impact Factor
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