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 (By similarity). Mechanistically, AIM2 senses DNA damage in the nucleus to mediate inflammasome assembly and inflammatory cell death (By similarity). 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 (By similarity). Pyroptosis mediated by the AIM2 inflammasome in response to DNA damage is dependent on GSDMD without involving IL1B and IL18 cytokine secretion (By similarity). Also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). Can also trigger PYCARD/ASC-dependent, caspase-1-independent cell death that involves caspase-8 (CASP8) (By similarity).
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 (By similarity). AIM2 suppresses cell proliferation by inhibiting phosphorylation of AKT1 at 'Ser-473', preventing AKT1 activation and AKT-mTOR signaling pathway (By similarity). Inhibits AKT1 phosphorylation both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) homeostasis by promoting their stability: acts by preventing AKT1 activation (By similarity). Its role in Treg homeostasis is important to restain autoimmune diseases (By similarity).
Subcellular locations: Cytoplasm, Inflammasome, Nucleus
Activated inflammasomes can aggregate in the cytosol as speck-like particles ( ). Activated inflammasomes can also aggregate in the nucleus in response to DNA damage: AIM2 is recruited to double-strand DNA breaks and mediates activation of the AIM2 inflammasome (By similarity).
Expressed in spleen, small intestine, peripheral blood leukocytes, and testis.