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Absent in melanoma 2 (AIM2) is a pattern recognition receptor (PRR) that can be used as a DNA receptor to sense DNA or bacterial infection and release into the cytoplasmic dsDNA to form AIM2 inflammatory bodies, therefore promoting the secretion and maturation of inflammatory cytokines such as IL-1β and IL-18 to initiate an innate immune response or induce cell pyrokosis. Studies found that AIM2 is abnormally expressed in various tumors such as melanoma, breast cancer, prostate cancer, lung cancer, liver cancer, and colorectal cancer (CRC), in which AIM2 expression is absent in CRC and there are many gene frameshifts and missense mutations. The expression of AIM2 is related to the prognosis of patients, but the mechanism of AIM2 affecting tumors is not clear.
Biological Function of AIM2
AIM2 was originally discovered in human melanoma cell lines and was named for this name because it is deleted in melanoma cell lines and can reverse the melanoma tumor phenotype. AIM2 is a member of the HIN-200 (hematopoietic IFN-inducible nuclear protein containing a 200-amino-acid repeat) family of proteins with two typical domains, a highly helical thermoprotein domain PYD (pyrin) Domain) N-terminal and contains two adjacent oligonucleotides/oligosaccharide-binding domain OB (oligonucleotide/oligosaccharide-binding domain) C-terminus. AIM2 can interacts with other proteins containing a death domain, a death effector domain, and a caspase recruitment domain (CARD) to activate multiple protein effects. So AIM2 plays an important role in innate immunity, inflammation, cell differentiation and apoptosis, and the development of tumors.
AIM2 is primarily localized to the cytoplasm and has a specific ability to recognize antigenic signals and plays a key role in initiating an innate immune response. AIM2 protein binds to ASC (apoptosis-associated speck like protein containing a caspase recruitment domain), induces ASC dimerization, and then interacts with Pro-Cas- pase-1 to form AIM2-ASC-Pro-Caspase-1 inflammatory complex (also known as the AIM2 inflammatory corpus), which in turn activates caspase-1, cleaves pro-IL-1β and pro-IL-18, leading to the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. Then it initiates an innate immune response. Caspase-1 simultaneously cleaves the substrate Gasdermine D, while the N-terminus of the latter induces cell-cause production while releasing mature IL-1β and IL18 out of the cell.
Figure 1. AIM2 induces nonclassical activation of the NLRP3 inflammasome. (Cunha, et al. 2017)
The formation and activation of inflammatory corposomes play an important role in host anti-infective immunity. According to different receptor proteins, they can be divided into NOD-like receptor family (NLR) NLRP1, NLRP3, NLRC4, NLRP6, NLRP12 and AIM2-like receptor family (ALR) such as AIM2, IFI16, pyrin inflammatory bodies, etc. AIM2 is the only member of the HIN-200 family that recognizes DNA-forming inflammatory bodies and activates Caspase-1. AIM2 also has certain limitations in the recognition of DNA. Although its recognition does not depend on the specific DNA sequence, it has certain requirements on the length of the DNA sequence. It can only be recognized by AIM2 when the DNA sequence reaches 80 bp. reaction.
AIM2 and Inflammation
AIM2 can regulate acute ionizing radiation and chemotherapy-induced colorectal inflammation. Acute ionizing radiation can induce apoptosis of a large number of proliferating cells such as bone marrow cells and gastrointestinal cells in a short period of time. Chemotherapy can also cause severe gastrointestinal toxicity, causeing an adverse inflammatory response, which affects its anti-tumor effect. When cells are damaged by acute ionizing radiation, AIM2 can form inflammatory corpuscles in the nucleus, inducing intestinal epithelial cells to stagnate. Blocking the action of AIM2 signaling, such as thalidomide or using the chemotherapeutic drug irinotecan (CPT-11) in AIM2-deficient mice, can significantly reduce drug side effects without affecting the anti-tumor effect of CPT-11. Thus, chemoradiotherapy has an important influence on the role of AIM2 in the development of inflammation.
Studies have found that AIM2 inflammatory bodies regulate intestinal balance through the IL-18/IL-22/STAT3 signaling pathway. Deletion of AIM2 leads to impaired IL-18 secretion, and decreased IL-22 binding protein (IL-22BP) in intestinal epithelial cells, which in turn causes loss of STAT3-dependent antimicrobial peptides (AMPs) Reg3 and Reg3-γ, causing intestinal homeostasis and inducing colon inflammation.
AIM2 and Tumor
AIM2 was originally found in human melanoma cells, and AIM2 mRNA was also detected in human spleen, small intestine, and peripheral blood leukocytes. Subsequent studies have found that IFN can increase the expression level of AIM2 in cells. Early studies suggest that AIM2 is a tumor suppressor that is expressed in melanoma, and its overexpression reverses the tumor phenotype of melanoma and inhibits the proliferation of fibroblasts. Although AIM2 has also been found to be highly expressed in cervical cancer, nasopharyngeal carcinoma, oral squamous cell carcinoma, and lung adenocarcinoma, AIM2 is under-represented in CRC, liver cancer, breast cancer, and prostate cancer. The frameshift and missense mutations of the AIM2 gene were also found in endometrial cancer, CRC, gastric cancer.
The study of human CRC cell HCT116 found that AIM2 can regulate cell cycle through PI3K/Akt pathway, block cell transition from G1 phase to S phase or block G2/M phase arrest, thereby inhibiting cell proliferation and promoting apoptosis. AIM2 inhibits DNA-PK activation, thereby inhibiting DNA-PK activation of Akt phosphorylation, whereas Akt inhibitor (API-2) reduces the number of polyps and tumors in AIM2-/- mice colon. Thus, AIM2 can reduce the risk of colorectal cancer (CRC) by affecting the cell proliferation and growth cycle by regulating the Akt pathway.
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