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

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

Author information

1
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
2
Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
3
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, TX, USA.
4
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, USA.
5
Department of Biological Science, Florida State University, Tallahassee, FL, USA.
6
Department of Chemistry, Texas A&M University, College Station, TX, USA.
7
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. pingwei@tamu.edu.

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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