A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1

Nucleic acids from bacteria or viruses induce potent immune responses in infected cells(1-4). The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses(5,6). Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor(7,8). It catalyses the synthesis of cyclic GMP-AMP (cGAMP)(9-12), which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis(13-15). STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase(8,16). The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK1(8,17-20). Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons(21). However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFN beta after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders.