AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Caspase 1; Cell Death; Cell Line; Cytoskeletal Proteins; Cytosol; DNA; Enzyme Activation; Humans; Inflammation; Mice; Nuclear Proteins; Poly dA-dT; Protein Binding; Vaccinia virus
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Nature. 2009 Mar 26;458(7237):514-8. Epub 2009 Jan 21. Link to article on publisher's site
Hornung, Veit; Ablasser, Andrea; Charrel-Dennis, Marie; Bauernfeind, Franz G.; Horvath, Gabor; Caffrey, Daniel R.; Latz, Eicke; and Fitzgerald, Katherine A., "AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC" (2009). Open Access Articles. 2183.