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

Nature | Mar 26, 2009

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.

Pubmed ID: 19158675 RIS Download

Mesh terms: Animals | Apoptosis Regulatory Proteins | Caspase 1 | Cell Death | Cell Line | Cytoskeletal Proteins | Cytosol | DNA | DNA-Binding Proteins | Enzyme Activation | Humans | Inflammation | Mice | Nuclear Proteins | Poly dA-dT | Protein Binding | Vaccinia virus

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Associated grants

  • Agency: NIAID NIH HHS, Id: R01 AI067497-05
  • Agency: NIAID NIH HHS, Id: R37 AI067497
  • Agency: NIAID NIH HHS, Id: R01 AI067497-04
  • Agency: NIAID NIH HHS, Id: R01 AI067497
  • Agency: NIAID NIH HHS, Id: AI-067497
  • Agency: NIAID NIH HHS, Id: R56 AI067497
  • Agency: NIAID NIH HHS, Id: AI-065483
  • Agency: NIAID NIH HHS, Id: R01 AI065483
  • Agency: NIAID NIH HHS, Id: R01 AI067497-03

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A biomedical and genomic research center that is independently governed that encompasses three types of organizational units: core member laboratories, programs and platforms which work together and with other collaborators to tackle critical problems in human biology and disease. Data and cutting edge software tools are generated and developed, and these tools analyze those data (increasingly large genome-related datasets) which is shared openly with the scientific community. The Broad faculty includes core members and associate members. All associate members hold primary appointments in a home department at one of the partner institutions, but are deeply involved in the scientific work and culture of the Broad Institute. It is formally affiliated with the Massachusetts Institute of Technology, Harvard University and its affiliated hospitals.

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