Cyclic GMP-AMP synthase (cGAS)–Stimulator of interferon genes (STING)–TANK-binding kinase 1 (TBK1)–Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway (cGAS–STING–TBK1–NF-κB pathway)

The Cyclic GMP-AMP synthase (cGAS)–Stimulator of interferon genes (STING)–TANK-binding kinase 1 (TBK1)–Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is a fundamental innate immune sensing mechanism that detects cytosolic double-stranded DNA (dsDNA) [1, 4]. Upon binding to dsDNA from viral, bacterial, or damaged host sources, cGAS catalyzes the synthesis of the second messenger 2',3'-cyclic GMP-AMP (cGAMP), which subsequently binds to and activates the adaptor protein STING on the endoplasmic reticulum [1, 10]. Activated STING translocates to the Golgi apparatus, where it recruits and activates the kinase TBK1, leading to the phosphorylation and nuclear translocation of transcription factors IRF3 and NF-κB [2, 6]. This cascade results in the robust production of type I interferons and pro-inflammatory cytokines, which are essential for antiviral defense and antitumor immunity [2, 9]. While this pathway is a multi-protein signaling axis rather than a single target, its components are major focuses for drug development; STING agonists are being tested as cancer immunotherapies, while inhibitors of cGAS, STING, or TBK1 are explored for treating autoimmune and neurodegenerative diseases [3, 5, 6, 15].

Other names

cGAS-STING axiscGAS-STING-TBK1 axisDNA-sensing pathwaySTING-NF-κB pathway

The pathway is activated when the enzyme cGAS senses cytosolic double-stranded DNA and produces the second messenger cGAMP, which binds to and activates the adaptor protein STING. Activated STING translocates from the endoplasmic reticulum to the Golgi apparatus, where it recruits the kinase TBK1 to phosphorylate and activate the transcription factors IRF3 and NF-κB, leading to the production of type I interferons and pro-inflammatory cytokines [1, 2, 6].