Stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) protein-protein interaction complex (STING-TBK1 complex)

The Stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) protein-protein interaction complex is a central component of the cGAS-STING signaling pathway, which is essential for the innate immune detection of cytosolic DNA (PubMed: 31439605). Upon binding of cyclic GMP-AMP (cGAMP), STING translocates from the endoplasmic reticulum to the Golgi apparatus, where it recruits TBK1 via its C-terminal tail (CTT) (PubMed: 30842659). This interaction facilitates the trans-autophosphorylation of TBK1 and the subsequent phosphorylation of STING and the transcription factor IRF3. The resulting signaling cascade induces the expression of type I interferons and other pro-inflammatory cytokines necessary for host defense against pathogens. Chronic or constitutive activation of this complex is a primary driver of autoinflammatory diseases, including STING-associated vasculopathy with onset in infancy (SAVI) and systemic lupus erythematosus (PubMed: 25099571). Consequently, small molecules designed to disrupt the STING-TBK1 interaction or inhibit TBK1 kinase activity within the complex are being developed as therapeutic agents for autoimmune and inflammatory conditions. Conversely, STING agonists that promote this interaction are being investigated in oncology to stimulate anti-tumor immunity (PubMed: 31941639).

Other names

STING-TBK1 interactionTMEM173-TBK1 complexSTING-TBK1 signalosomeStimulator of interferon genes-TANK-binding kinase 1 complex

Modulation of the STING-TBK1 complex through either direct inhibition of the STING-TBK1 protein-protein interaction, inhibition of TBK1 kinase activity, or agonistic/antagonistic binding to the STING protein to alter complex formation and downstream signaling.