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. 2025 Sep 27;34(1):68–96. doi: 10.1016/j.ymthe.2025.09.041

Figure 2.

Figure 2

Nucleic acid-sensing receptors of the innate immune system

Nucleic acid sensors of the innate immune system, including AIM2, cGAS, TLRs, RIG-I, and MDA5, recognize specific DNA and RNA molecules. AIM2, cGAS, RIG-I, and MDA5 recognize cytoplasmic nucleic acids. AIM2 forms inflammasomes with ligands and ASCs, leading to the activation of caspase-1 and production of IL-1β and IL-18. The ER-resident protein STING receives cGAMP produced by cGAS. It interacts with TRAF3 to induce IRF3 phosphorylation via TBK1, or associates with TRAF6 to activate NF-κB through IKKα/β. RIG-I and MDA5 associate with the mitochondrial MAVS adaptor protein, triggering the activation of IRF3, IRF7, and NF-κB through TRAF3- and TRAF6-dependent pathways. TLR3, TLR7, and TLR9 sense nucleic acids in endosomes. TLR3 signals through TRIF, which is associated with TRAF3- and TRAF6-dependent pathways. TLR7 and TLR9 signal through the MyD88 adaptor protein, which is associated with TRAF3 and TRAF6 to activate IRF3, IRF7, and NF-κB. The resulting intracellular signaling cascades transcriptionally induce the expression of genes encoding pro-inflammatory cytokines and type I interferons. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a CARD; ATP, adenosine 5′-triphosphate; CARD, caspase recruitment domain; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cGAS, cGAMP synthase; dsDNA/RNA, double-stranded DNA/RNA; ER, endoplasmic reticulum; GTP, guanosine 5′-triphosphate; IKKα/β, inhibitor of nuclear factor κ kinase subunit α/β; IL-1β/18, interleukin-1β/18; IRF3/7, interferon regulatory factor 3/7; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; PYD, pyrin domain; RIG-I, retinoic acid-inducible gene I; ssDNA/RNA, single-stranded DNA/RNA; STING, stimulation of interferon genes protein; TLR3/7/9, Toll-like receptor 3/7/9; TBK1, TANK-binding kinase 1; TRAF3/6, tumor necrosis factor receptor-associated factor 3/6; TRIF, Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β.