Schematic illustration of IRF transcription factor activation and type I IFN gene induction by innate immune receptor signaling pathways (IMAGE)

Immunity & Inflammation

Schematic illustration of IRF transcription factor activation and type I IFN gene induction by innate immune receptor signaling pathways

Caption

TLR4 recognizes bacterial-derived lipopolysaccharides and activates IRF3 via the adapter protein TRIF, contributing to the induction of type I IFN genes. Within endosomes, TLR3, TLR7, and TLR9 recognize double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and hypomethylated DNA, respectively. TLR3 activates IRF3 via the adapter protein TRIF, while TLR7 and TLR9 in pDCs activate IRF7 via the MyD88 and IKK complexes. In the cytoplasm, DNA-recognizing receptors such as cGAS, DAI, IFI16, and DDX41 recognize dsDNA and activate IRF3 via the adapter protein STING on the endoplasmic reticulum or ERGIC, which in turn activates TBK1 and IKKe, leading to the induction of type I IFN genes. RLRs such as RIG-I and MDA5 recognize dsRNA and activate IRF3 and IRF7 via mitochondrial adapter proteins MAVS. Although not depicted in this figure, there is evidence that IRF5 is also involved in type I IFN gene induction in pDCs, while IRF1 contributes to the induction of type I IFNs in cDCs. There is also evidence that IRF8 is involved in the expression of type I IFN genes without its interaction with MyD88 in pDCs (see text). In the nucleus, hnRNPA2B1 recognizes DNA released by DNA viruses, forms homodimers, and is demethylated by JMJD6. Subsequently, hnRNPA2B1 translocates to the cytoplasm and activates the STING-TBK1-IRF3 pathway. IFI16 and RPSA also function as nuclear DNA sensors. Abbreviations: IRF, IFN regulatory factor; TLR, Toll-like receptor; TRIF, TIR domain-containing adapter IFN-b inducer; pDCs, plasmacytoid dendritic cells; cDCs, conventional DCs; MyD88, Myeloid differentiation primary response gene 88; TBK1, TANK-binding kinase 1; IKK, IkB kinase; RLRs, RIG-I-like receptors; cGAS, cyclic GMP-AMP synthase; STING, stimulator of IFN genes; ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartment; A2B1, hnRNPA2B1; JMJD6, Jumonji domain containing 6.

Credit

Professor Tadatsugu Taniguchi from The University of Tokyo, Japan Image source link: https://link.springer.com/article/10.1007/s44466-025-00019-9

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