Stimulator of interferon genes (STING) signaling pathway (STING pathway)

The Stimulator of interferon genes (STING) signaling pathway, involving TANK-binding kinase 1 (TBK1) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is a central axis of the innate immune system [1] (Motwani et al., 2019, Nature Reviews Genetics). It is primarily activated by the presence of cytosolic DNA, which is sensed by cyclic GMP-AMP synthase (cGAS) to produce the second messenger cGAMP [2] (Hopfner & Hornung, 2020, Nature Reviews Molecular Cell Biology). Upon binding cGAMP, STING translocates from the endoplasmic reticulum to the Golgi, where it recruits and activates TBK1 [3] (Liu et al., 2015, Nature Immunology). This kinase then phosphorylates the transcription factors IRF3 and NF-κB, promoting the expression of Type I interferons and pro-inflammatory cytokines that orchestrate an immune response [4] (Abe & Barber, 2014, Journal of Virology). In monocytes and other immune cells, this pathway is vital for anti-viral defense and anti-tumor immunity, but its dysregulation is implicated in autoinflammatory conditions like STING-associated vasculopathy with onset in infancy (SAVI) and systemic lupus erythematosus [1]. Therapeutic strategies include STING agonists to enhance immune responses in oncology and STING or TBK1 inhibitors to dampen pathological inflammation in autoimmune diseases [5] (Sivick et al., 2018, Cell Reports).

Other names

cGAS-STING pathwaySTING-TBK1-NF-κB axisSTING-mediated signalingCytosolic DNA-sensing pathway

Activation of STING by cyclic dinucleotides leads to the recruitment and activation of TBK1, which in turn phosphorylates IRF3 and the IKK complex, resulting in the nuclear translocation of IRF3 and NF-κB to drive the expression of interferons and pro-inflammatory cytokines [1] (Motwani et al., 2019, Nature Reviews Genetics); [4] (Abe & Barber, 2014, Journal of Virology).