AIM2
Description
The AIM2 (absent in melanoma 2) is a protein-coding gene located on chromosome 1.
Interferon-inducible protein AIM2, also known as absent in melanoma 2 or simply AIM2, is a protein that in humans is encoded by the AIM2 gene. AIM2 is a cytoplasmic sensor found in hematopoietic cells that recognizes the presence of double-stranded DNA (dsDNA) of microbial or host cellular origin. AIM2-like receptor (ALR) family was founded on AIM2 and now consists of four members in the human genome. Activated AIM2 recruits apoptosis-associated speck-like protein containing a CARD (ASC), resulting in caspase-1 binding, and forming of the AIM2 inflammasome. This signaling contributes to the defense against bacterial and viral DNA. The AIM2 inflammasome can also be an integral component of the AIM2-PANoptosome to drive PANoptosis. Proteins belonging to the ALR family usually contain an N-terminal pyrin (PYD) domain, and one or two HIN domains. AIM2 consists of two domains connected through a long linker: an N-terminal PYD domain (amino acids 1-87), and a C-terminal HIN-200 domain (amino acids 138–337). The PYD domain mediates homotypic protein-protein interaction, while the HIN domain binds to DNA with its two tandem oligonucleotide/oligosaccharide binding (OB) folds. AIM2 is a component of the innate immune system that functions as a cytoplasmic dsDNA sensor playing a role in antiviral and antibacterial defenses, as well as in autoimmune diseases involving self DNA. Together with the adaptor ASC protein AIM2 forms a caspase-1 activating complex known as the AIM2 inflammasome. This AIM2 inflammasome can also be an integral component of a larger cell death-inducing complex called the AIM2-PANoptosome that drives PANoptosis.
AIM2 is a sensor component of the AIM2 inflammasome, which is activated in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to pyroptosis. AIM2 acts as a recognition receptor (PRR) that 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. AIM2 detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner. It is 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. AIM2 also acts as a regulator of neurodevelopment via its role in the DNA damage response, 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. AIM2 is also a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection. It can also trigger PYCARD/ASC- dependent, caspase-1-independent cell death that involves caspase-8 (CASP8).
AIM2 is also known as PYHIN4.
