HGNC Approved Gene Symbol: AIM2
Cytogenetic location: 1q23.1-q23.2 Genomic coordinates (GRCh38) : 1:159,055,051-159,147,132 (from NCBI)
AIM2 is an intracellular DNA sensor involved in proinflammatory cytokine production (Yan et al., 2018).
Chromosome alterations in malignant melanoma most frequently include translocations and deletions on chromosome 1 or 6 (see AIM1; 601797). Using subtractive cDNA selection to identify novel cDNAs expressed exclusively in a chromosome-suppressed melanoma cell line, DeYoung et al. (1997) isolated a novel cDNA, which they termed AIM2. AIM2 encodes a deduced 344-amino acid protein that contains a conserved sequence domain of approximately 200 amino acids shared with interferon-inducible genes (e.g., IFI16, 147586, and MNDA, 159553) as well as a tyrosine kinase phosphorylation site. Northern blot analysis revealed expression of a 2-kb AIM2 transcript in spleen, small intestine, and peripheral blood leukocytes, as well as a slightly larger transcript in testis.
Choubey et al. (2000) found that AIM2 was expressed as a 39-kD protein following in vitro transcription/translation in rabbit reticulocyte lysate or transfection in a murine epithelial cell line. Cell fractionation showed that AIM2 localized primarily to the cytoplasm of transfected mouse cells.
By FISH, DeYoung et al. (1997) mapped the AIM2 gene to chromosome 1q22, where IFI16 and MNDA are also located.
DeYoung et al. (1997) found that overexpression of AIM2 reversed the tumorigenic phenotype in a melanoma cell line. IFNG (147570) induced expression of AIM2 in the HL60 cell line.
Choubey et al. (2000) found that AIM2 overexpression retarded proliferation of murine fibroblasts. AIM2 bound mouse p202, for which there is no human ortholog, and binding required the N-terminal dimerization motif of p202. Choubey et al. (2000) concluded that AIM2 may exert the growth inhibitory effect of interferon.
Fernandes-Alnemri et al. (2009) demonstrated that AIM2, an interferon-inducible HIN200 family member, senses cytoplasmic DNA by means of its C-terminal oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD; 606838) through its N-terminal pyrin domain to activate caspase-1 (147678). The interaction of AIM2 with ASC also leads to the formation of 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 nonresponsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Fernandes-Alnemri et al. (2009) concluded that their results showed that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization.
Using mouse and human cells, Hornung et al. (2009) identified the PYHIN (pyrin and HIN domain-containing protein) family member 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 to activate both NF-kappa-B (see 164011) and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Hornung et al. (2009) concluded that collectively, their observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.
Listeria monocytogenes is detected in the cytosol by NLRC4 (606831) and NLRP3 (606416), which induce assembly of the inflammasome. Inflammasomes serve as platforms for activation of CASP1, which mediates the processing and secretion of IL1B (147720) and IL18 (600953) precursors. Using biochemical and genetic approaches, Warren et al. (2010) identified AIM2 as a third inflammasome detector for L. monocytogenes and its DNA.
Hu et al. (2016) showed that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, Hu et al. (2016) found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death.
Naik et al. (2017) reported a prolonged memory to acute inflammation that enables mouse epithelial stem cells (EpSCs) to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fueling this memory is Aim2, which encodes an activator of the inflammasome. The absence of Aim2 or its downstream effectors, caspase-1 (147678) and interleukin-1-beta (147720), erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
Yan et al. (2018) showed that mycobacterial infection of Aim2 -/- mice reciprocally induced overreactive IFN-beta (147640) and depressive IFN-gamma responses, leading to higher infection burdens and more severe pathology compared with controls. Furthermore, Aim2 deficiency enhanced production of type I IFN signaling upon bacille Calmette-Guerin (BCG) infection or stimulation with various DNA forms in bone marrow-derived dendritic cells and bone marrow-derived macrophages, indicating that the Aim2 inflammasome signaling pathway inhibits production of type I IFN during stimulation. Further investigation revealed that such inhibition of IFN-beta induction was dependent on downstream Aim2 inflammasome signaling in the context of the Sting (612374) pathway, as the activated form of Asc interacted with Sting. The N-terminal transmembrane domains or the CTT domain of Sting were required for interaction with Asc. Interaction of Asc and Sting impeded association of Sting with Tbk1 (604834), resulting in inhibition of IFN-beta production in response to stimulation.
Lammert et al. (2020) showed that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioral abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D (GSDMD; 617042)-mediated form of cell death known as pyroptosis. Lammert et al. (2020) observed pronounced AIM2 inflammasome activation in neurodevelopment and found that defects in this sensor of DNA damage resulted in anxiety-related behaviors in mice. Furthermore, they showed that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL1 (see 147760) and/or IL18 (600953). Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, Lammert et al. (2020) found that defective AIM2 inflammasome signaling resulted in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 led to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporated into the adult brain. Lammert et al. (2020) concluded that their findings identified the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.
Choubey, D., Walter, S., Geng, Y., Xin, H. Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2 (absent in melanoma) gene from the 200-gene family. FEBS Lett. 474: 38-42, 2000. [PubMed: 10828447] [Full Text: https://doi.org/10.1016/s0014-5793(00)01571-4]
DeYoung, K. L., Ray, M. E., Su, Y. A., Anzick, S. L., Johnstone, R. W., Trapani, J. A., Meltzer, P. S., Trent, J. M. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15: 453-457, 1997. [PubMed: 9242382] [Full Text: https://doi.org/10.1038/sj.onc.1201206]
Fernandes-Alnemri, T., Yu, J.-W., Datta, P., Wu, J., Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458: 509-513, 2009. [PubMed: 19158676] [Full Text: https://doi.org/10.1038/nature07710]
Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D. R., Latz, E., Fitzgerald, K. A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458: 514-518, 2009. [PubMed: 19158675] [Full Text: https://doi.org/10.1038/nature07725]
Hu, B., Jin, C., Li, H.-B., Tong, J., Ouyang, X., Cetinbas, N. M., Zhu, S., Strowig, T., Lam, F. C., Zhao, C., Henao-Mejia, J., Yilmaz, O., Fitzgerald, K. A., Eisenbarth, S. C., Elinav, E., Flavell, R. A. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354: 765-768, 2016. [PubMed: 27846608] [Full Text: https://doi.org/10.1126/science.aaf7532]
Lammert, C. R., Frost, E. L., Bellinger, C. E., Bolte, A. C., McKee, C. A., Hurt, M. E., Paysour, M. J., Ennerfelt, H. E., Lukens, J. R. AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment. Nature 580: 647-652, 2020. [PubMed: 32350463] [Full Text: https://doi.org/10.1038/s41586-020-2174-3]
Naik, S., Larsen, S. B., Gomez, N. C., Alaverdyan, K., Sendoel, A., Yuan, S., Polak, L., Kulukian, A., Chai, S., Fuchs, E. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550: 475-480, 2017. Note: Erratum: Nature 560: E2, 2018. [PubMed: 29045388] [Full Text: https://doi.org/10.1038/nature24271]
Warren, S. E., Armstrong, A., Hamilton, M. K., Mao, D. P., Leaf, I. A., Miao, E. A., Aderem, A. Cutting edge: cytosolic bacterial DNA activates the inflammasome via Aim2. J. Immun. 185: 818-821, 2010. [PubMed: 20562263] [Full Text: https://doi.org/10.4049/jimmunol.1000724]
Yan, S., Shen, H., Lian, Q., Jin, W., Zhang, R., Lin, X., Gu, W., Sun, X., Meng, G., Tian, Z., Chen, Z. W., Sun, B. Deficiency of AIM2-ASC signal uncovers the STING-driven overreactive response of type I IFN and reciprocal depression of protective IFN-gamma immunity in mycobacterial infection. J. Immun. 200: 1016-1026, 2018. Note: Erratum: J. Immun. 204: 472 only, 2020. [PubMed: 29255077] [Full Text: https://doi.org/10.4049/jimmunol.1701177]