A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Academic Article uri icon


  • Nucleic acids from bacteria or viruses induce potent immune responses in infected cells1-4. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses5,6. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor7,8. 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 axis13-15. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase8,16. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK18,17-20. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons21. 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 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.

published proceedings

  • Nature

altmetric score

  • 51.984

author list (cited authors)

  • Zhao, B., Du, F., Xu, P., Shu, C., Sankaran, B., Bell, S. L., ... Li, P.

citation count

  • 137

complete list of authors

  • Zhao, Baoyu||Du, Fenglei||Xu, Pengbiao||Shu, Chang||Sankaran, Banumathi||Bell, Samantha L||Liu, Mengmeng||Lei, Yuanjiu||Gao, Xinsheng||Fu, Xiaofeng||Zhu, Fanxiu||Liu, Yang||Laganowsky, Arthur||Zheng, Xueyun||Ji, Jun-Yuan||West, A Phillip||Watson, Robert O||Li, Pingwei

publication date

  • January 2019

published in