A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1
Abstract
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,more »
- Authors:
-
- 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)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1577334
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 569; Journal Issue: 7758; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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., and Li, Pingwei. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. United States: N. p., 2019.
Web. doi:10.1038/s41586-019-1228-x.
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. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. United States. https://doi.org/10.1038/s41586-019-1228-x
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., and Li, Pingwei. Wed .
"A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1". United States. https://doi.org/10.1038/s41586-019-1228-x. https://www.osti.gov/servlets/purl/1577334.
@article{osti_1577334,
title = {A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1},
author = {Zhao, Baoyu and Du, Fenglei and Xu, Pengbiao and Shu, Chang and Sankaran, Banumathi and Bell, Samantha L. and Liu, Mengmeng and Lei, Yuanjiu and Gao, Xinsheng and Fu, Xiaofeng and Zhu, Fanxiu and Liu, Yang and Laganowsky, Arthur and Zheng, Xueyun and Ji, Jun -Yuan and West, A. Phillip and Watson, Robert O. and Li, Pingwei},
abstractNote = {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.},
doi = {10.1038/s41586-019-1228-x},
journal = {Nature (London)},
number = 7758,
volume = 569,
place = {United States},
year = {Wed May 22 00:00:00 EDT 2019},
month = {Wed May 22 00:00:00 EDT 2019}
}
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Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells
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Works referencing / citing this record:
Regulation of cGAS- and RLR-mediated immunity to nucleic acids
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