| AIM2, or absent in melanoma 2, is an interferon‑inducible PYHIN family cytosolic sensor that detects aberrant double‑stranded DNA in the cytoplasm and assembles a multi‑protein inflammasome platform that links genomic and pathogen-derived DNA signals to caspase activation, cytokine maturation and inflammatory cell death. The protein contains an N‑terminal pyrin domain that mediates homotypic interactions with the adaptor ASC and a C‑terminal HIN200 domain that binds dsDNA in a sequence‑independent manner, allowing AIM2 to nucleate higher‑order complexes once a sufficient length of cytoplasmic DNA is present. Upon dsDNA recognition, the HIN domain engages the DNA backbone and promotes oligomerization of AIM2 along the DNA scaffold, which in turn drives pyrin domain clustering and recruitment of ASC into helical filaments that serve as a platform for procaspase‑1 assembly and activation. Activated caspase‑1 cleaves pro‑IL‑1β and pro‑IL‑18 into their mature secreted forms and processes Gasdermin D to trigger pyroptotic cell death, establishing AIM2 as a key upstream component of innate immune responses to cytosolic DNA from pathogens such as Francisella, Listeria, Mycobacterium, cytomegalovirus, vaccinia virus, Aspergillus and Plasmodium species. AIM2 inflammasome assembly relies on high‑order filamentous architectures rather than simple stoichiometric complexes, and regulatory factors can modulate filament nucleation and stability to tune the threshold and kinetics of inflammasome activation. AIM2 engagement of ASC can also recruit and activate caspase‑8 alongside caspase‑1, allowing the same inflammasome platform to drive both apoptotic and pyroptotic pathways; lower dsDNA doses favor caspase‑8–dependent apoptosis, whereas higher DNA burdens more rapidly engage caspase‑1–mediated pyroptosis, indicating a dose‑dependent switch in death modality controlled by AIM2. AIM2 also has inflammasome‑independent roles that include regulation of intestinal stem cell proliferation and gut microbiota composition in colorectal cancer models, placing AIM2 as a factor in tumor suppression and epithelial homeostasis where its expression constrains excessive proliferative signaling. Dysregulated AIM2 activity toward self‑DNA contributes to autoimmune and autoinflammatory conditions such as psoriasis, dermatitis and arthritis, where inappropriate sensing of endogenous cytoplasmic DNA leads to chronic IL‑1β/IL‑18 production and sustained inflammatory damage. In cancer, AIM2 exhibits context‑dependent effects: loss or reduced expression can relieve checks on stem cell proliferation and support colorectal tumor development, while aberrant AIM2 inflammasome activity can create a pro‑tumorigenic inflammatory microenvironment in other settings. |
