Article

Hornung, V. 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: 42.35). 02/2009; 458(7237):514-8. DOI: 10.1038/nature07725
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Eicke Latz, Mar 15, 2014
0 Followers
 · 
196 Views
  • Source
    • "E-mail: harri.alenius@ttl.fi double-stranded DNA (Hornung et al., 2009) or the NLRP3 inflammasome which senses and responds to different dangerassociated molecular patterns (DAMPs) such as crystalline and fibrous materials (Duewell et al., 2010; Hornung et al., 2008; Palomäki et al., 2011). Indeed, it has been claimed that NLRP3 inflammasome activation is the crucial step for inflammation induced by engineered nanomaterials (ENM) both in vitro and in vivo, especially in the inflammation induced by hazardous types of fibers (Bhattacharya et al., 2009; Palomäki et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: doi: 10.3109/17435390.2014.969346
    Nanotoxicology 10/2014; DOI:10.3109/17435390.2014.969346 · 7.34 Impact Factor
  • Source
    • "Membrane bound and intracellular PRRs cooperate to fully activate IL-1b and IL-18 release. Absent in melanoma 2 (AIM2) has been recently identified as a cytosolic double-stranded DNA (dsDNA) sensor, contributing to the inflammasome complex by combining with ASC and caspase-1 [6]. The ligands of AIM2 are cytosolic dsDNAs, coming from viruses, bacteria, and the host. "
    Journal of Hepatology 10/2014; 62(1). DOI:10.1016/j.jhep.2014.10.003 · 10.40 Impact Factor
  • Source
    • "RLRs Viral dsRNA, polyA:C ROS Tal et al. (2009) ALRs dsDNA, polyA:T Cytosolic DNA Adamczak et al. (2012), Hornung et al. (2009) (e.g., IRAK4). IRAK activation signals engagement of TRAF6, an E3 ubiquitin ligase. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as “damage associated molecular patterns” (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors. Broad expression of these PRRs in the CNS and the release of DAMPs in and around sites of injury suggest an important role for these receptor families in mediating post-injury inflammation. Considerable data now show that PRRs are among the first responders to CNS injury and activation of these receptors on microglia, neurons, and astrocytes triggers an innate immune response in the brain and spinal cord. Here we discuss how the various PRR families are activated and can influence injury and repair processes following CNS injury.
    Experimental Neurology 08/2014; 258:5–16. DOI:10.1016/j.expneurol.2014.01.001 · 4.62 Impact Factor
Show more