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Cited by 447interferon and immune responsesImmune Response and InflammationCytokine Signaling Pathways and Interactions

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

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Zhao, Baoyu, Du, Fenglei, Xu, Pengbiao, Shu, Chang, Sankaran, Banumathi, Bell, Samantha L., Liu, Mengmeng, Lei, Yuanjiu +10 more·2019·Nature
DOI 10.1038/s41586-019-1228-xPMC PMC6596994
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Abstract

Nucleic acids from bacteria or viruses induce potent immune responses in infected cells 1-4. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses 5,6. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor 7,8. 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 axis 13-15. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase 8,16. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK1 8,17-20. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons 21. 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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  • On reaching the Golgi, STING recruits TBK1, which activates IRF3 and NF-κB, leading to expression of ISGs, type I interferons and other inflammatory cytokines.

    “On reaching the Golgi compartment, STING then recruits TBK1, which then activates IRF3 and NF-κB, leading to the expression of interferon-stimulated genes (ISGs), type I interferons and other inflammatory cytokines (e.g., IL-6, IL-12).393–396”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [394]

    The proposed model in Extended Data Fig. 7 says STING oligomerizes at ER or Golgi membranes, recruits TBK1, and enables TBK1-dependent IRF-3 activation and IFN-β transcription. It does not specify that recruitment occurs only after STING reaches the Golgi, or describe NF-κB activation, ISG expression, or production of other inflammatory cytokines such as IL-6 and IL-12. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Levels of phosphorylated TBK1 (Ser172) are increased in aged mouse brains.

    “The levels of phosphorylated TBK1 (Ser172; pTBK1)—the major kinase responsible for signal transduction downstream of STING19,20—were increased in aged mouse brains (Fig. 2d).”

    From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [20]

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Research works printed but not linked: 25

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Authors
Zhao, B., Du, F., Xu, P., Shu, C., Sankaran, B., Bell, S. L., Liu, M., Lei, Y., Gao, X., Fu, X., Zhu, F., Liu, Y., Laganowsky, A., Zheng, X., Ji, J.-Y., West, A. P., Watson, R. O., & Li, P.
Affiliations
  • Texas A&M University (US)
  • Lawrence Berkeley National Laboratory (US)
  • Texas A&M Health Science Center (US)
  • Florida State University (US)
Corresponding author
Li, Pingwei
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-05
Volume
569
Issue
7758
Pages
718-722
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1228-x
PMC
PMC6596994
OpenAlex
W2945775408
Cited by
447
References
5
Citations by year
2026: 74 · 2025: 87 · 2024: 82 · 2023: 64 · 2022: 55 · 2021: 43 · 2020: 33 · 2019: 9
FWCI
14.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
  • Cancer Prevention and Research Institute of Texas (RP150454)
  • Florida State University (S10 RR025080, S10 OD018142)
  • University of Pittsburgh
  • National Institutes of Health (DE-AC02–05CH11231, 1s10od018142-01, AI145287)
  • Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
  • National Institute of General Medical Sciences (DE-AC02-05CH11231)
  • National Institute of Allergy and Infectious Diseases (R01AI125512, R01AI145287)
  • National Institute of Dental and Craniofacial Research (R01DE026101)
  • National Center for Research Resources (S10RR025080)
  • Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., AC02–05CH11231)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
STING, TBK1, cGAMP, cGAS, IRF3, type I interferon signaling, innate immune recognition, STING agonist
MeSH terms
STING Protein, Enzyme Activation, Humans, Membrane Proteins, Models, Molecular, Mutation, Nucleotides, Cyclic, Protein Binding, Signal Transduction, Interferon-beta, Conserved Sequence, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Amino Acid Motifs, HEK293 Cells

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