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

Baoyu Zhao, Fenglei Du, Pengbiao Xu, Chang Shu, Banumathi Sankaran, Samantha L. Bell, Mengmeng Liu, Yuanjiu Lei, Xinsheng Gao, Xiaofeng Fu, Fanxiu Zhu, Yang Liu, Arthur Laganowsky, Xueyun Zheng, Jun-Yuan Ji, A. Phillip West, Robert O. Watson and Pingwei Li ()
Additional contact information
Baoyu Zhao: Texas A&M University
Fenglei Du: Texas A&M University
Pengbiao Xu: Texas A&M University
Chang Shu: Texas A&M University
Banumathi Sankaran: Lawrence Berkeley National Laboratory
Samantha L. Bell: Texas A&M University Health Science Center
Mengmeng Liu: Texas A&M University Health Science Center
Yuanjiu Lei: Texas A&M University Health Science Center
Xinsheng Gao: Texas A&M University Health Science Center
Xiaofeng Fu: Florida State University
Fanxiu Zhu: Florida State University
Yang Liu: Texas A&M University
Arthur Laganowsky: Texas A&M University
Xueyun Zheng: Texas A&M University
Jun-Yuan Ji: Texas A&M University Health Science Center
A. Phillip West: Texas A&M University Health Science Center
Robert O. Watson: Texas A&M University Health Science Center
Pingwei Li: Texas A&M University

Nature, 2019, vol. 569, issue 7758, 718-722

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1228-x

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