AIM2

Proteins belonging to 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. == Function ==

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. The interaction is mainly electrostatic, where positively charged amino acid residues are coordinating with phosphates and sugar moieties on DNA backbone. Binding of dsDNA displaces PYD domain, which then engages the downstream inflammasome adaptor protein ASC through homotypic PYD-PYD interactions. ASC is a bipartite PYD-CARD-containing protein. CARD domain of ASC recruits procaspase-1 (CARD-CARD interaction) to the complex creating the basic structural elements of the AIM2 inflammasome. Caspase-1 autoactivates and processes cleavage of pro-IL-1β, pro-IL-18, and gasdermin D. The N-terminal fragment of gasdermin D induces pyroptosis that allows mature cytokines IL-1β, and IL-18 to be released from the cell. AIM2 can also induce PANoptosis, a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer. To form the PANoptosome, the AIM2 inflammasome further interacts with caspase-8, FADD, RIPK3, and RIPK1 in response to specific pathogens, including Francisella novicida and herpes simplex virus 1 (HSV1), to drive PANoptosis. == Regulation ==

Regulation of inflammasome assembly is essential for cellular homeostasis maintenance. AIM2 activation is inhibited by the mouse protein p202 that consists of two HIN domains and lacks the PYD. ASC protein is not recruited due to the absence of PYD domain. The HIN1 domain binds to DNA, whereas HIN2 domain interacts with AIM2. HIN2 domain does not block the DNA binding surface of AIM2, hence, DNA binding affinity of AIM2 remains unaffected. It is believed that binding of p202 to DNA and AIM2 might attain a balance between host defense and pathological DNA-induced inflammation. When both p202 and AIM2 are present in equal amounts, there is a competition for dsDNA binding. A novel transcript isoform of human IFI16-designated IFI16-β has been also shown to inhibit the AIM2 inflammasome assembly. Its domain structure is similar to that of mouse p202 as it contains two HIN domains. Analogously it interacts with AIM2, competes in dsDNA binding, and disrupts ASC recruitment. According to studies of p202 and IFI16-β, it appears that proteins expressing two HIN domains bind to dsDNA more robustly than proteins containing a single HIN domain. Regarding post-translational modifications, there is limited knowledge. However, it has been reported that TRIM11 binds AIM2 and leads to its degradation. Hence, it might be a negative regulator of the AIM2 inflammasome. ==Clinical relevance==

A broad range of microbes is sensed by AIM2, leading to protective inflammasome- or PANoptosome-mediated host responses. Recent publications have shown that AIM2 inflammasome also plays roles in non-infectious diseases. Infection Bacteria Bacterial DNA is released into the cytoplasm during infection of a host cell, where it is recognized by AIM2 and other cytoplasmic DNA sensors. AIM2 has been shown to recognize a number of pathogenic bacteria – Francisella tularensis, Listeria monocytogenes, Streptococcus pneumoniae, Mycobacterium species, Porphyromonas gingivalis, Staphylococcus aureus, Brucella abortus, and Chlamydia muridarum. In addition, AIM2 assembles the AIM2-PANoptosome complex in response to Francisella novicida, inducing inflammatory cell death, PANoptosis. and the protozoan Plasmodium berghei. Cancer The gene encoding AIM2 was originally isolated from human melanoma cells. == References ==