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Open Access Publications from the University of California

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

  • Author(s): 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
  • et al.
Abstract

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 IFNβ 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.

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