Stimulator of interferon genes–TANK-binding kinase 1 protein–protein interface (STING–TBK1 interface)

The Stimulator of interferon genes–TANK-binding kinase 1 (STING–TBK1) protein–protein interface is a critical regulatory junction in the cGAS-STING signaling pathway, which detects cytosolic DNA as a signal of infection or cellular damage (UniProt Q86WV6, Q9UHD2). Upon activation by cyclic GMP-AMP (cGAMP), STING dimers undergo a conformational change and translocate from the endoplasmic reticulum to the Golgi apparatus, where they recruit TBK1 via a conserved pLxIS motif located in the STING C-terminal tail (Liu et al., 2015, Science). This interaction facilitates the trans-autophosphorylation of TBK1 and the subsequent phosphorylation of the transcription factor IRF3, which is essential for the induction of Type I interferons and other pro-inflammatory cytokines (Zhang et al., 2019, Nature). In oncology, pharmacological agonists are used to stabilize or enhance this interface to promote anti-tumor immunity, while in autoinflammatory conditions like SAVI, small molecule inhibitors or disruptors of this interface are being developed to prevent constitutive immune activation. The interface represents a high-precision target for modulating innate immunity, as it sits downstream of DNA sensing but upstream of broad transcriptional responses.

Other names

STING-TBK1 complexTMEM173-TBK1 interaction siteSTING-TBK1 signalosomeSTING C-terminal tail-TBK1 interface

Modulation of the recruitment and activation of TBK1 by STING to either enhance or suppress downstream IRF3 phosphorylation and Type I interferon gene expression.