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

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

Authors

  • Hornung V
  • Ablasser A
  • Charrel-Dennis M
  • Bauernfeind F
  • Horvath G
  • Caffrey DR
  • Latz E
  • Fitzgerald KA

Journal

Nature

Publication Data

March 26, 2009

Associated Grants

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

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