Understanding Innate Immune DNA Sensing Pathways: STING, AIM2, and Interferon Regulation
Innate immunity detects foreign DNA to activate immune responses. Cells use specialized sensors to recognize cytosolic DNA and trigger signaling pathways. These mechanisms help identify infections and cellular stress.
The Stimulator of Interferon Genes (STING) pathway is a key cytosolic DNA sensing mechanism. It is activated by cyclic GMP-AMP synthase (cGAS), which binds to double-stranded DNA (dsDNA) and produces cyclic GMP-AMP (cGAMP). cGAMP binds to STING on the endoplasmic reticulum (ER), leading to its activation and translocation to the Golgi. STING recruits and activates TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 translocates to the nucleus and induces the expression of type I interferons and other immune-related genes.
AIM2 Inflammasome
Absent in Melanoma 2 (AIM2) is a cytosolic DNA sensor that forms an inflammasome complex upon recognizing dsDNA. AIM2 interacts with the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), leading to the activation of caspase-1. Activated caspase-1 processes pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), promoting an inflammatory response. The AIM2 inflammasome is crucial for detecting intracellular bacterial and viral DNA.
Cytosolic DNA sensing pathways, particularly the STING and AIM2 pathways, play a crucial role in immune defense by recognizing foreign DNA and initiating signaling cascades. These pathways are tightly regulated to maintain immune balance and prevent excessive activation.
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Regulation of Interferon Responses
Multiple mechanisms regulate DNA sensing pathways to prevent excessive immune activation:
Negative Feedback: Proteins such as ubiquitin-specific protease 13 (USP13) and tripartite motif-containing protein 38 (TRIM38) degrade STING or modify signaling components to limit activation.
Autophagy: Damaged cellular components and mislocalized DNA are degraded by autophagy to prevent unwanted immune responses.
Post-TranslationalModifications: Phosphorylation,ubiquitination,and
SUMOylation modify STING, TBK1, and IRF3 to fine-tune immune responses.