AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA

By T. Fernandes-Alnemri, Je-Wook Yu, Jianghong Wu, P. Datta, E. Alnemri. Nature, 2009

1,870 citations recorded by the source corpus.

Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome, which activates caspase-1 leading to maturation of pro-interleukin-1β and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/06c8756107ad1734e100e65ad4dd6255b488c3c9

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Citations in the corpus

Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. (2013, background): “Typhimurium or cytosolic poly(dA-dT) DNA, which are dependent on the NLRC4 and AIM2 inflammasomes, respectively, and independent of NLRP3 (Figures S2A–S2F) (Fernandes-Alnemri et al., 2009; Mariathasan et al., 2004).”
The Inflammasome: A Caspase-1 Activation Platform Regulating Immune Responses and Disease Pathogenesis (2009, background): “In contrast, activation of caspase-1 by cytosolic double-stranded DNA is not mediated by NLRP3 but involves the pyrin domain–containing protein AIM2, a member of the HIN-200 family (hematopoietic interferon-inducible nuclear protein), and AS”
Immune sensing of DNA (2013, neutral): “…(AIM2) and IFN-g-inducible (IFI16) have been demonstrated to be essential for distinct DNA-activated innate responses and have been proposed to be DNA sensors (Hornung et al., 2009; Fernandes-Alnemri et al., 2009; Bürckstümmer et al., 2009; Roberts et al., 2009; Unterholzner et al., 2010).”
IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma associated herpesvirus infection (2011, background): “ASC functions as an adaptor molecule recruiting and interacting with “sensor” proteins such as NLRP3 or AIM2 (Burckstummer et al., 2009; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Martinon et al., 2002).”
Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death (2017, neutral): “In some experiments, cell culture supernatants were precipitated by methanol/chloroform as described previously 24,59 .”
Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation* (2012, methodology): “The immortalizedWT, Nlrp3 knock-out (Nlrp3-KO) and Myd88/Trif double knockout (Myd88/Trif-dKO) macrophages were described previously (6, 9, 10).”
RIG-I dependent sensing of poly(dA-dT) via the induction of an RNA polymerase III transcribed RNA intermediate (2009, neutral): “However, AIM2 does not regulate the transcription of genes encoding type I interfero”