AIM2

Summary

AIM2 (absent in melanoma 2, HGNC:357) is a protein-coding gene on chromosome 1q23.1-q23.2, encoding Interferon-inducible protein AIM2 (O14862). Sensor component of the AIM2 inflammasome, which mediates inflammasome activation in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to subsequent pyroptosis.

AIM2 is a member of the IFI20X /IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2.

Source: NCBI Gene 9447 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 53 total
• Druggable target: yes
• MANE Select transcript: NM_004833

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:357
Approved symbol	AIM2
Name	absent in melanoma 2
Location	1q23.1-q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PYHIN4
Ensembl gene	ENSG00000163568
Ensembl biotype	protein_coding
OMIM	604578
Entrez	9447

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000368129, ENST00000368130, ENST00000411768, ENST00000481829, ENST00000695579, ENST00000695580, ENST00000695581, ENST00000695582, ENST00000850621, ENST00000913842

RefSeq mRNA: 2 — MANE Select: NM_004833 NM_001348247, NM_004833

CCDS: CCDS1181

Canonical transcript exons

ENST00000368130 — 6 exons

Exon	Start	End
ENSE00001699341	159063486	159063674
ENSE00003636769	159065910	159066329
ENSE00003707095	159073238	159073519
ENSE00003709677	159068568	159068701
ENSE00004282350	159076633	159076766
ENSE00004282354	159062484	159062718

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 90.78.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9532 / max 375.9360, expressed in 372 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15362	4.5956	340
15363	0.1343	89
15361	0.0902	39
15364	0.0471	7
15366	0.0371	9
15367	0.0352	10
15365	0.0137	3

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	90.78	gold quality
spleen	UBERON:0002106	89.94	gold quality
sperm	CL:0000019	89.50	gold quality
monocyte	CL:0000576	88.79	gold quality
mononuclear cell	CL:0000842	88.17	gold quality
leukocyte	CL:0000738	87.62	gold quality
vermiform appendix	UBERON:0001154	86.47	gold quality
male germ cell	CL:0000015	86.11	gold quality
superficial temporal artery	UBERON:0001614	84.50	gold quality
blood	UBERON:0000178	84.00	gold quality
pituitary gland	UBERON:0000007	83.77	gold quality
epithelium of nasopharynx	UBERON:0001951	83.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.18	gold quality
tonsil	UBERON:0002372	82.01	gold quality
caecum	UBERON:0001153	81.91	gold quality
adenohypophysis	UBERON:0002196	81.82	gold quality
choroid plexus epithelium	UBERON:0003911	81.17	gold quality
granulocyte	CL:0000094	80.64	gold quality
cortical plate	UBERON:0005343	79.57	gold quality
ileal mucosa	UBERON:0000331	79.46	gold quality
ganglionic eminence	UBERON:0004023	77.63	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.47	gold quality
colonic epithelium	UBERON:0000397	76.88	gold quality
gingival epithelium	UBERON:0001949	74.91	silver quality
ventricular zone	UBERON:0003053	74.67	gold quality
small intestine	UBERON:0002108	73.42	gold quality
bone marrow cell	CL:0002092	72.56	gold quality
gingiva	UBERON:0001828	72.26	silver quality
gall bladder	UBERON:0002110	69.34	gold quality
rectum	UBERON:0001052	69.33	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	88.83
E-ANND-3	yes	16.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

16 targeting AIM2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-5586-5P	96.29	68.02	685

Literature-anchored findings (GeneRIF, showing 40)

• AIM-2 antigen is expressed in glioblastoma multiforme (GBM) in primary cultured cells and established GBM cell lines (PMID:15076139)
• AIM2 could homodimerise via the amino-terminal (PAAD/DAPIN) region and heterodimerise with the related IFI 16 protein (PMID:15582594)
• AIM2 associates with tumor suppression activity (PMID:16432157)
• inactivation of AIM2 by genetic and epigenetic mechanisms is frequent in Mismatch repair -deficient colorectal cancers, thus suggesting that AIM2 is a mutational target relevant for the progression of MSI-H colorectal cancers. (PMID:17726700)
• observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1 (PMID:19158675)
• identification of AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1 (PMID:19158676)
• The AIM2 influenced core 1 mucin-type O-glycosylation differentially, downregulation by AIM2. (PMID:19293232)
• AIM2 mediates reduction of cell proliferation by cell cycle arrest, thereby conferring an invasive phenotype in colon cancer cells. (PMID:19795419)
• [REVIEW] role of AIM2 in innate immunity against F. tularensis in particular, and how infection of macrophages with this pathogen is thought to activate AIM2 (PMID:20401524)
• Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts (PMID:21471287)
• supragingival and subgingival biofilms differentially regulate the gene expressions of AIM2 in gingival fibroblasts (PMID:21550598)
• data indicate that AIM2 mediates both IFN-gamma dependent and independent induction of several interferon-stimulated genes (PMID:21804607)
• The author show that Francisella mutant strains deficient for membrane-associated proteins or deficient for genes involved in O-antigen or LPS biosynthesis lyse more intracellularly, thus activating AIM2-dependent pyroptosis. (PMID:21883803)
• Human keratinocytes express a functional AIM2 inflammasome which triggers a strong IL-1beta release in response to cytosolic dsDNA. (PMID:22092578)
• a pathway activating DNA damage signaling plays an important independent role in detecting intracellular foreign DNA, thereby complementing the induction of IFN and activation of the AIM2 inflammasome (PMID:22140256)
• expression of AIM2 and IFI16 may have oncogenic activities in the OSCC cells that have inactivated the p53 system. (PMID:22320325)
• crystal structures of their HIN domains in complex with double-stranded (ds) DNA. (PMID:22483801)
• End binding protein 1 directly interacted with AIM2 and ASC in vitro and in vivo. (PMID:22869553)
• Our data highlight the dynamics of epidermal AIM2 expression, showing Langerhans cell and melanocyte-restricted expression in normal epidermis but a pronounced induction in subpopulations of epidermal keratinocytes under inflammatory conditions. (PMID:23171461)
• Data suggest that AIM2 (absent in melanoma 2) expression is correlated with the immune clearance of hepatitis B virus (HBV) in the host. (PMID:23376086)
• AIM2 might act as an important DNA sensor and a potential biomarker for apopDNA-induced macrophage functional maturation and SLE disease (PMID:23479181)
• Novel structural features of the AIM2 pyrin domain and insights into the potential mechanisms of domain interactions important for AIM2 autoinhibition and inflammasome assembly. (PMID:23530044)
• Binding of Human papillomavirus 16 DNA leads to AIM2 inflammasome activation. (PMID:23764897)
• Vascular endothelial/smooth muscle cells are able to respond to inflammatory signals by upregulation of AIM2 expression, indicating a role of AIM2 in vascular pathogenesis. (PMID:23790454)
• this study was to investigate the mRNA levels of AIM2 and ASC in a lymphocyte cell line (Jurkat) before and after MiR-143 introducing. (PMID:23811549)
• AIM2 mRNA levels were higher in benign prostate hyperplasia (BPH)than normal prostate; levels of AIM2 mRNA were lower in clinical tumor specimens; constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells compared with BPH cells; Implication that AIM2 inflammasome has a fundamental role in the generation of prostatic diseases (PMID:23864729)
• Studies indicate that the HIN (hematopoietic expression, interferon-inducible nature, and nuclear localization) domains exhibit either absent in melanoma2 (Aim2) HIN-like or p202 HINa-like modes of DNA binding. (PMID:24164899)
• Ethanol inhibits activation of NLRP3 and AIM2 inflammasomes in human macrophages–a novel anti-inflammatory action of alcohol. (PMID:24244322)
• These results, together with the reported data on p202 HINb, lead to an interaction model for full-length p202 and dsDNA which provides a conceivable mechanism for the negative regulation of Aim2 inflammasome activation by p202. (PMID:24419611)
• Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms (PMID:24618883)
• caspase-1, IL-1beta, and IL-18 are regulated by AIM2, which mediates inflammation-associated renal damage in hepatitis B virus-associated glomerulonephritis (PMID:24701032)
• Lack of Absent in Melanoma 2 expression is associated with colorectal cancer. (PMID:24729378)
• Thus, autophagy may function as a negative counter-regulatory mechanism for HMGB1-DNA complex-induced inflammasome activation, and provide a checkpoint to limit the development of inflammation. (PMID:24971542)
• These results suggest that AIM2 expressed in human dental pulp plays an important role in the immune defense by activating the inflammasome signaling pathway. (PMID:24986444)
• EB1 has a role in linking AIM2 inflammasomes with autophagy-dependent secretion (PMID:25164813)
• activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. (PMID:25173967)
• The comparison shows mouse AIM2 PYD domain adopts a unique alpha2-alpha3 helix conformation distinct from its human homologues, but similar to the pyrin domain of human NLRP10/PYNOD, which belongs to another family. (PMID:25888795)
• pyrin domain drives both filament formation and dsDNA binding (PMID:26197926)
• analysis of a subset of inflammasome receptors including NLRP3, NLRC4 and AIM2 that triggers formation of the micrometer-sized spherical supramolecular complex called the ASC speck (PMID:26258904)
• A significant upregulation of the PYHIN inflammasomes AIM2 and IFI16 in active inflammatory bowel disease versus controls was found. (PMID:26313692)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aim2	ENSMUSG00000037860
rattus_norvegicus	Aim2	ENSRNOG00000003480

Paralogs (3): MNDA (ENSG00000163563), PYHIN1 (ENSG00000163564), IFI16 (ENSG00000163565)

Protein

Protein identifiers

Interferon-inducible protein AIM2 — O14862 (reviewed: O14862)

Alternative names: Absent in melanoma 2

All UniProt accessions (3): A0A8Q3WLZ2, O14862, Q5T3W0

UniProt curated annotations — full annotation on UniProt →

Function. Sensor component of the AIM2 inflammasome, which mediates inflammasome activation in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to subsequent pyroptosis. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. Acts as a recognition receptor (PRR): specifically recognizes and binds dsDNA in the cytosol, and mediates the formation of the inflammasome polymeric complex composed of AIM2, CASP1 and PYCARD/ASC. Recruitment of pro-caspase-1 (proCASP1) to the AIM2 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion. In some cells, CASP1 activation mediates cleavage and activation of GSDMD, triggering pyroptosis without promoting cytokine secretion. Detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner. Involved in the DNA damage response caused by acute ionizing radiation by mediating pyroptosis of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks. Mechanistically, AIM2 senses DNA damage in the nucleus to mediate inflammasome assembly and inflammatory cell death. Also acts as a regulator of neurodevelopment via its role in the DNA damage response: acts by promoting neural cell death in response to DNA damage in the developing brain, thereby purging genetically compromised cells of the central nervous system. Pyroptosis mediated by the AIM2 inflammasome in response to DNA damage is dependent on GSDMD without involving IL1B and IL18 cytokine secretion. Also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection. Can also trigger PYCARD/ASC-dependent, caspase-1-independent cell death that involves caspase-8 (CASP8). Also acts as a tumor suppressor independently of its role in inflammatory response. Able to suppress overt cell proliferation in enterocytes: restricts stem cell proliferation in the intestinal mucosa in an inflammasome-independent manner, contributing to a decrease in the likelihood of colorectal cancer development. AIM2 suppresses cell proliferation by inhibiting phosphorylation of AKT1 at ‘Ser-473’, preventing AKT1 activation and AKT-mTOR signaling pathway. Inhibits AKT1 phosphorylation both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase. Also acts as a key regulator of regulatory T-cells (Treg) homeostasis by promoting their stability: acts by preventing AKT1 activation. Its role in Treg homeostasis is important to restain autoimmune diseases.

Subunit / interactions. Self-associates; forms homooligomers in response to cytosolic double-stranded DNA (dsDNA) and the dsDNA seems to serve as oligomerization platform. Component of AIM2 inflammasome, which consists of a signal sensor component (AIM2), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis). Interacts with PYDC5; disrupts assembly of the AIM2 inflammasome complex. Interacts with EIF2AK2/PKR. Interacts with MAPRE1. Interacts with IFI16. Interacts with isoform IFI16-beta of IFI16; preventing the interaction between AIM2 and PYCARD/ASC. Interacts with RACK1; promoting association with PP2A phosphatase and dephosphorylation of AKT1. Interacts with TRIM11; promoting AIM2 recruitment to autophagosomes and autophagy-dependent degradation. (Microbial infection) Interacts with human herpesvirus 8 protein SOX/ORF37; this interaction inhibits AIM2 polymerization and subsequent inflammasome activation.

Subcellular location. Cytoplasm. Inflammasome. Nucleus.

Tissue specificity. Expressed in spleen, small intestine, peripheral blood leukocytes, and testis.

Post-translational modifications. Degraded via selective autophagy following interaction with TRIM11.

Activity regulation. Inactive in absence of double-stranded DNA (dsDNA). Homooligomerizes upon binding to dsDNA, dsDNA serving as an oligomerization platform. AIM2 requires large dsDNA to generate a structural template that couples dsDNA ligand-binding and homooligomerization. Homooligomerization is followed by recruitment of PYCARD/ASC to initiate speck formation (nucleation). AIM2 and PYCARD/ASC homooligomer filaments assemble bidirectionally and the recognition between AIM2 and PYCARD/ASC oligomers occurs in a head-to-tail manner. Clustered PYCARD/ASC nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization and activation. Active CASP1 then specifically processes protein precursors, such as gasdermin-D (GSDMD), IL1B and IL18, leading to the release of mature cytokines in the extracellular milieu or pyroptosis, depending on cell type. AIM2 can be activated in response to events that cause genomic DNA (HIV protease inhibitor nelfinavir) or mitochondrial DNA release in the cytoplasm (such as Perfluoroalkyl substance pollutants or cholesterol overload). Activation of the AIM2 inflammasome is inhibited by isoform IFI16-beta of IFI16, which prevents the interaction between AIM2 and PYCARD/ASC. Activation of the AIM2 inflammasome is inhibited by TRIM11, which promotes autophagy-dependent degradation of AIM2.

Domain organisation. The pyrin domain mediates homotypic interaction with PYCARD/ASC. The HIN-200 domain mediates dsDNA binding via electrostatic interactions.

Induction. By IFNG/IFN-gamma and IFNB1/IFN-beta.

Miscellaneous. Defects in AIM2 may be a cause of microsatellite unstable colon cancers.

Similarity. Belongs to the HIN-200 family.

RefSeq proteins (2): NP_001335176, NP_004824* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004020	DAPIN	Domain
IPR004021	HIN200/IF120x	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR040205	HIN-200	Family

Pfam: PF02758, PF02760

UniProt features (64 total): mutagenesis site 32, strand 14, helix 11, domain 2, sequence variant 2, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4O7Q	X-RAY DIFFRACTION	1.82
3VD8	X-RAY DIFFRACTION	2.07
3RN5	X-RAY DIFFRACTION	2.5
3RN2	X-RAY DIFFRACTION	2.55
7K3R	ELECTRON MICROSCOPY	3.2
6MB2	ELECTRON MICROSCOPY	5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14862-F1	84.18	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (32):

Position	Phenotype
23	impaired homooligomerization.
27–28	in mut1; abolished interaction with pycard/asc.
27	abolished ability to homooligomerize.
27	strongly impaired ability to homooligomerize.
27	impaired ability to homooligomerize.
36	impaired homooligomerization.
46	impaired homooligomerization.
50	impaired double-stranded dna (dsdna)-binding, preventing homooligomerization.
73	impaired ability to form aim2 inflammasome filaments in response to double-stranded dna (dsdna).
75	impaired ability to nucleate with pycard/asc.
147	strongly reduced ability to homooligomerize upon double-stranded dna (dsdna)-binding.
160	impairs dna binding; when associated with a-160; a-k162; a-163; a-198; a-204. impairs dna binding; when associated with
162	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
163	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
165	impairs dna binding.
167	strongly reduced ability to homooligomerize upon double-stranded dna (dsdna)-binding.
173	impaired double-stranded dna (dsdna)-binding, preventing homooligomerization.
198	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
204	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
244	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
251	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
258	impaired double-stranded dna (dsdna)-binding, preventing homooligomerization.
272	strongly reduced ability to homooligomerize upon double-stranded dna (dsdna)-binding.
309	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a
311	impairs dna binding; when associated with a-160; a-162; a-163; a-198; a-204. impairs dna binding; when associated with a

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-844615	The AIM2 inflammasome
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-622312	Inflammasomes

MSigDB gene sets: 300 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_BEHAVIOR, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_INFLAMMASOMES, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_RESPONSE_TO_INTERFERON_BETA, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (27): activation of innate immune response (GO:0002218), pattern recognition receptor signaling pathway (GO:0002221), positive regulation of defense response to virus by host (GO:0002230), immune response (GO:0006955), DNA damage response (GO:0006974), brain development (GO:0007420), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), positive regulation of interleukin-1 beta production (GO:0032731), tumor necrosis factor-mediated signaling pathway (GO:0033209), cellular response to interferon-beta (GO:0035458), T cell homeostasis (GO:0043029), innate immune response (GO:0045087), positive regulation of inflammatory response (GO:0050729), regulation of behavior (GO:0050795), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), protein maturation (GO:0051604), defense response to virus (GO:0051607), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), neuron cellular homeostasis (GO:0070050), pyroptotic inflammatory response (GO:0070269), cellular response to xenobiotic stimulus (GO:0071466), AIM2 inflammasome complex assembly (GO:0140970), pyroptosome complex assembly (GO:1904270), immune system process (GO:0002376), inflammatory response (GO:0006954), cellular response to cytokine stimulus (GO:0071345), pyroptotic cell death (GO:0141201)

GO Molecular Function (7): double-stranded DNA binding (GO:0003690), signaling adaptor activity (GO:0035591), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), cysteine-type endopeptidase activator activity (GO:0140608), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), site of double-strand break (GO:0035861), AIM2 inflammasome complex (GO:0097169), nucleus (GO:0005634), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	2
Inflammasomes	1
Immune System	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
inflammatory response	2
cytoplasm	2
intracellular membrane-bounded organelle	2
activation of immune response	1
positive regulation of innate immune response	1
innate immune response-activating signaling pathway	1
regulation of defense response to virus by host	1
immune system process	1
response to stimulus	1
cellular response to stress	1
central nervous system development	1
animal organ development	1
head development	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
lymphocyte homeostasis	1
immune response	1
defense response to symbiont	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
behavior	1
regulation of multicellular organismal process	1
gene expression	1
protein metabolic process	1
defense response	1
response to virus	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of intracellular signal transduction	1
cellular homeostasis	1
DNA binding	1
protein-macromolecule adaptor activity	1
signaling receptor activity	1

Protein interactions and networks

STRING

1544 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIM2	MEFV	O15553	999
AIM2	NLRP3	Q96P20	999
AIM2	CASP1	P29466	999
AIM2	NLRC4	Q9NPP4	999
AIM2	PYCARD	Q9ULZ3	998
AIM2	NLRP1	Q9C000	998
AIM2	NLRP6	P59044	996
AIM2	NAIP	Q13075	989
AIM2	NLRP12	P59046	981
AIM2	NLRP2	Q9NX02	963
AIM2	RIGI	O95786	933
AIM2	PYDC1	Q8WXC3	921
AIM2	IFI16	Q16666	917
AIM2	NLRP7	Q8WX94	909
AIM2	IL18	Q14116	898

IntAct

29 interactions, top by confidence:

A	B	Type	Score
AIM2	PYCARD	psi-mi:“MI:0915”(physical association)	0.890
PYCARD	AIM2	psi-mi:“MI:0915”(physical association)	0.890
PYCARD	AIM2	psi-mi:“MI:0407”(direct interaction)	0.890
AIM2	PYCARD	psi-mi:“MI:0407”(direct interaction)	0.890
AIM2	AIM2	psi-mi:“MI:0407”(direct interaction)	0.660
AIM2	AIM2	psi-mi:“MI:0915”(physical association)	0.660
CASP1	AIM2	psi-mi:“MI:0915”(physical association)	0.490
SQSTM1	AIM2	psi-mi:“MI:0403”(colocalization)	0.430
AIM2	SQSTM1	psi-mi:“MI:0914”(association)	0.430
EIF2AK2	AIM2	psi-mi:“MI:0915”(physical association)	0.400
AIM2	NPM1	psi-mi:“MI:0915”(physical association)	0.400
AIM2		psi-mi:“MI:0915”(physical association)	0.400
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
AIM2	DDX39A	psi-mi:“MI:0914”(association)	0.350
AIM2	Map1lc3a	psi-mi:“MI:0403”(colocalization)	0.270
AIM2	LAMP1	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (115): APPBP2 (Two-hybrid), AIM2 (Co-localization), TRIM11 (Affinity Capture-Western), AIM2 (Affinity Capture-Western), AIM2 (Affinity Capture-Western), AIM2 (Two-hybrid), AIM2 (Two-hybrid), NPM1 (Proximity Label-MS), ADAR (Affinity Capture-MS), ADNP (Affinity Capture-MS), AIM2 (Affinity Capture-MS), ALDH3A2 (Affinity Capture-MS), BANF1 (Affinity Capture-MS), BCL11A (Affinity Capture-MS), BCL11B (Affinity Capture-MS)

ESM2 similar proteins: A6H5X4, B2RX14, D0QMC3, D3ZF42, F6QRE9, O14862, O35368, P0C6Y7, P0DOV1, P0DOV2, P23497, P41218, Q13342, Q15361, Q16666, Q17RS7, Q3KRF1, Q504N7, Q5H9K5, Q5I0E2, Q5RD14, Q5RF97, Q5T4T6, Q5VYS8, Q5W0A0, Q62187, Q66JT0, Q6K0P9, Q6NYJ3, Q6ZMT9, Q7RTT4, Q80VH0, Q86X53, Q8BUH8, Q8BV49, Q8BVK9, Q8C0V1, Q8CGE8, Q8NDB2, Q8SPH9

Diamond homologs: D0QMC3, O14862, O35368, P0DOV1, P0DOV2, P41218, Q16666, Q3V3Q4, Q504N7, Q5RD14, Q6K0P9, Q8BV49, Q8CGE8, Q8SPH9, Q91VJ1, Q9R002, W6CW81

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AIM2	“form complex”	“AIM2 inflammasome”	binding
DAMPS	“up-regulates activity”	AIM2
PAMPs	“up-regulates activity”	AIM2

Disease & clinical

Clinical variants and AI predictions

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1108 predictions. Top by Δscore:

Variant	Effect	Δscore
1:159066169:T:TA	donor_gain	1.0000
1:159068702:C:CC	acceptor_gain	1.0000
1:159074593:C:CT	acceptor_gain	1.0000
1:159171849:GGACG:G	donor_gain	1.0000
1:159171850:GACG:G	donor_gain	1.0000
1:159171850:GACGG:G	donor_gain	1.0000
1:159171854:G:GG	donor_gain	1.0000
1:159065909:CCTT:C	donor_gain	0.9900
1:159066325:TCAGG:T	acceptor_gain	0.9900
1:159066326:CAGG:C	acceptor_gain	0.9900
1:159066326:CAGGC:C	acceptor_gain	0.9900
1:159066327:AGG:A	acceptor_gain	0.9900
1:159066328:GG:G	acceptor_gain	0.9900
1:159066330:C:CC	acceptor_gain	0.9900
1:159068698:TCAA:T	acceptor_gain	0.9900
1:159068699:CAA:C	acceptor_gain	0.9900
1:159068699:CAAC:C	acceptor_gain	0.9900
1:159068706:T:TC	acceptor_gain	0.9900
1:159069309:A:C	acceptor_gain	0.9900
1:159074593:C:T	acceptor_gain	0.9900
1:159074594:A:T	acceptor_gain	0.9900
1:159076800:C:A	donor_gain	0.9900
1:159171851:ACG:A	donor_gain	0.9900
1:159171852:CG:C	donor_gain	0.9900
1:159171853:GG:G	donor_gain	0.9900
1:159171855:T:A	donor_loss	0.9900
1:159171858:G:GG	donor_gain	0.9900
1:159065903:AACTT:A	donor_loss	0.9800
1:159065904:ACTT:A	donor_loss	0.9800
1:159065905:CTTAC:C	donor_loss	0.9800

AlphaMissense

2281 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:159066123:G:C	F201L	0.977
1:159066123:G:T	F201L	0.977
1:159066125:A:G	F201L	0.977
1:159065922:A:C	F268L	0.966
1:159065922:A:T	F268L	0.966
1:159065924:A:G	F268L	0.966
1:159066195:A:C	F177L	0.959
1:159066195:A:T	F177L	0.959
1:159066197:A:G	F177L	0.959
1:159066124:A:G	F201S	0.957
1:159063495:G:C	S332R	0.953
1:159063495:G:T	S332R	0.953
1:159063497:T:G	S332R	0.953
1:159066165:G:C	F187L	0.945
1:159066165:G:T	F187L	0.945
1:159066167:A:G	F187L	0.945
1:159066181:G:T	A182D	0.934
1:159063549:G:C	F314L	0.933
1:159063549:G:T	F314L	0.933
1:159063551:A:G	F314L	0.933
1:159066191:C:G	A179P	0.929
1:159066182:C:G	A182P	0.926
1:159066225:A:C	F167L	0.911
1:159066225:A:T	F167L	0.911
1:159066227:A:G	F167L	0.911
1:159066196:A:G	F177S	0.907
1:159066124:A:C	F201C	0.904
1:159066072:G:C	F218L	0.899
1:159066072:G:T	F218L	0.899
1:159066074:A:G	F218L	0.899

dbSNP variants (sampled 300 via entrez): RS1000022960 (1:159125183 C>T), RS1000034745 (1:159131051 G>A), RS1000048590 (1:159147593 G>A), RS1000102774 (1:159121415 A>G,T), RS1000149550 (1:159099806 C>T), RS1000175032 (1:159119058 G>A), RS1000191342 (1:159072566 A>G), RS1000198813 (1:159082265 T>C), RS1000258528 (1:159124966 T>A), RS1000359600 (1:159136498 T>C), RS1000359619 (1:159105558 G>A), RS1000390093 (1:159076375 A>C), RS1000432350 (1:159072087 T>C), RS1000484870 (1:159071749 A>G,T), RS1000496519 (1:159080309 A>C)

Disease associations

OMIM: gene MIM:604578 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_657	Obesity-related traits	1.000000e-06
GCST002743_1	Neutrophil count in HIV-infection	3.000000e-06
GCST008479_5	Psoriasis	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake
EFO:0004833	neutrophil count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630802 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Absent in melanoma (AIM)-like receptors (ALRs)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctane sulfonic acid	decreases reaction, increases activity, increases secretion, decreases response to substance, increases expression	2
Lipopolysaccharides	affects expression, increases expression, affects reaction, affects response to substance	2
Nickel	decreases expression, increases expression	2
TL8-506	affects cotreatment, increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	1
perfluorooctanoic acid	increases expression	1
artenimol	affects reaction, increases expression, increases secretion, affects response to substance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
bafilomycin A1	affects cotreatment, increases abundance, increases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Demecolcine	increases expression	1
Diuron	decreases expression	1
Formaldehyde	increases expression	1
Glucose	increases expression	1
Melitten	increases expression, increases reaction	1
Methotrexate	affects response to substance	1
Plant Extracts	affects expression, affects reaction	1
Tretinoin	increases expression	1
Vincristine	increases expression	1
Nanotubes, Carbon	increases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4628096	Binding	Inhibition of AIM2 inflammasome (unknown origin) activation in bone marrow derived macrophages assessed as inhibition of poly(dA:dT)-induced IL-1beta secretion at 5 uM by ELISA	Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7VW	Abcam Raji AIM2 KO	Cancer cell line	Male
CVCL_B9WE	Abcam THP-1 AIM2 KO	Cancer cell line	Male
CVCL_C6YF	Abcam PC-3 AIM2 KO	Cancer cell line	Male
CVCL_E1PY	HAP1 AIM2 (-) 1	Cancer cell line	Male
CVCL_E1PZ	HAP1 AIM2 (-) 2	Cancer cell line	Male
CVCL_E1Q0	HAP1 AIM2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

51 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome