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

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

doi:10.1038/s41586-019-1228-x

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

Journal Article · Wed May 22 00:00:00 EDT 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-1228-x· OSTI ID:1577334

Zhao, Baoyu ^[1]; Du, Fenglei ^[1]; Xu, Pengbiao ^[1]; Shu, Chang ^[1]; Sankaran, Banumathi ^[2]; Bell, Samantha L. ^[1]; Liu, Mengmeng ^[3]; Lei, Yuanjiu ^[3]; Gao, Xinsheng ^[3]; Fu, Xiaofeng ^[4]; Zhu, Fanxiu ^[4]; Liu, Yang ^[1]; Laganowsky, Arthur ^[1]; Zheng, Xueyun ^[1]; Ji, Jun -Yuan ^[3]; West, A. Phillip ^[3]; Watson, Robert O. ^[3]; Li, Pingwei ^[1]

Texas A & M Univ., College Station, TX (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Texas A & M Univ. Health Science Center, College Station, TX (United States)
Florida State Univ., Tallahassee, FL (United States)

Nucleic acids from bacteria or viruses induce potent immune responses in infected cells. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor. It catalyses the synthesis of cyclic GMP-AMP (cGAMP), which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK1. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons. 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. Furthermore, 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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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1577334

Journal Information:: Nature (London), Vol. 569, Issue 7758; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 130 works

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