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

Journal Article · · Nature (London)
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  1. Texas A & M Univ., College Station, TX (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. Texas A & M Univ. Health Science Center, College Station, TX (United States)
  4. Florida State Univ., Tallahassee, FL (United States)
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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.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1577334
Journal Information:
Nature (London), Journal Name: Nature (London) Journal Issue: 7758 Vol. 569; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (3)

Additional file 1 of MARCH1 negatively regulates TBK1-mTOR signaling pathway by ubiquitinating TBK1 dataset January 2024
Regulation of cGAS- and RLR-mediated immunity to nucleic acids journal December 2019
STING Activation and its Application in Immuno-Oncology journal November 2019

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59 BASIC BIOLOGICAL SCIENCES