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

By V. Hornung, A. Ablasser, M. Charrel-Dennis, F. Bauernfeind, Gabor L Horvath, Daniel R. Caffrey, E. Latz, Katherine A. Fitzgerald. Nature, 2009

2,650 citations recorded by the source corpus.

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 IL1β 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-κB 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8ecf4c8c137641bd8a8d91e911cb1fa7ec2b40f2

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In Immunology

1. T. Kanneganti
2. J. Tschopp
3. M. Lamkanfi
4. G. Núñez
5. Shizuo Akira
6. Kate Schroder
7. V. Dixit
8. T. Mogensen

In Molecular Biology

1. T. Kanneganti
2. J. Tschopp
3. M. Lamkanfi
4. G. Núñez
5. Kate Schroder
6. V. Dixit
7. E. Latz
8. D. Tang

Citations in the corpus

• Role of pyroptosis in inflammation and cancer (2022, background): “AIM2 is another type of inflammasome that directly binds to cytosolic dsDNA from DNA viruses through HIN-200 domains, unlike NLR inflammasomes [57, 58].”
• Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase (2013, positive): “, 2011), and members of the HIN-200 (hematopoietic interferon-inducible nuclear proteins) family such as AIM2 (absent in melanoma 2) (Hornung et al., 2009; Bürckstümmer et al., 2009; Fernandes-Alnemri et al., 2009) and IFI16 (interferon-inducible protein 16) (Unterholzner et al.”
• The inflammasomes. (2010, positive): “…of the HIN-200 family member, AIM2, as a cytosolic double-stranded DNA (dsDNA) sensor that induces caspase-1-dependent IL-1 b maturation is an important advance in the inflammasome field (Bu¨rckstu¨mmer et al., 2009; Fer-nandes-Alnemri et al., 2009; Hornung et al., 2009; Roberts et al., 2009).”
• Inflammasomes and their roles in health and disease. (2012, background): “Although AIM2 may not encounter selfDNA under normal conditions, transfection of synthetic and mammalian dsDNA nevertheless induced activation of the AIM2 inflammasome (Burckstummer et al. 2009, Fernandes-Alnemri et al. 2009, Hornung et al. 2009).”
• Coronavirus infections and immune responses (2020, background): “[24] [25] [26] The second subclass is essential to reproduction and embryo regeneration.”
• Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression1 (2009, methodology): “Quantitative real-time PCR was performed as described (12).”
• 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).”
• Inflammasomes in neuroinflammatory and neurodegenerative diseases (2019, background): “…of type III secretion systems (T3SS) of bacterial pathogens (Franchi et al, 2006; Miao et al, 2006, 2010); AIM2 physically binds cytosolic doublestranded DNA (dsDNA) (Hornung et al, 2009); and pyrin indirectly responds to toxins that covalently inactivate the small GTPase RhoA (Xu et al, 2014).”
• 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).”