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

Nature. 2019 May;569(7758):718-722. doi: 10.1038/s41586-019-1228-x. Epub 2019 May 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs*
  • Conserved Sequence*
  • Crystallography, X-Ray
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Interferon-beta / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Mutation
  • Nucleotides, Cyclic / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction

Substances

  • Membrane Proteins
  • Nucleotides, Cyclic
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human