STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition
Abstract
How the central innate immune protein, STING, is activated by its ligands remains unknown. In this study, using structural biology and biochemistry, we report that the metazoan second messenger 2'3'-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2'3'-cGAMP signaling. In conclusion, our insights explain the tight control of STING signaling given varying background activation signals and provide a therapeutic hypothesis for autoimmune syndrome treatment.
- Authors:
-
- Stanford Univ., CA (United States)
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1546886
- Grant/Contract Number:
- AC02-76SF00515; P41GM103393; 5 T32 GM007276
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Cell
- Additional Journal Information:
- Journal Volume: 178; Journal Issue: 2; Journal ID: ISSN 0092-8674
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; STING; cGAMP; 2′3′-cGAMP; innate immunity; STING associated vasculopathy with onset in infancy; SAVI; TMEM173; cyclic-di-GMPcyclic-di-AMP; cyclic-dinucleotide
Citation Formats
Ergun, Sabrina L., Fernandez, Daniel, Weiss, Thomas M., and Li, Lingyin. STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition. United States: N. p., 2019.
Web. doi:10.1016/j.cell.2019.05.036.
Ergun, Sabrina L., Fernandez, Daniel, Weiss, Thomas M., & Li, Lingyin. STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition. United States. https://doi.org/10.1016/j.cell.2019.05.036
Ergun, Sabrina L., Fernandez, Daniel, Weiss, Thomas M., and Li, Lingyin. Thu .
"STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition". United States. https://doi.org/10.1016/j.cell.2019.05.036. https://www.osti.gov/servlets/purl/1546886.
@article{osti_1546886,
title = {STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition},
author = {Ergun, Sabrina L. and Fernandez, Daniel and Weiss, Thomas M. and Li, Lingyin},
abstractNote = {How the central innate immune protein, STING, is activated by its ligands remains unknown. In this study, using structural biology and biochemistry, we report that the metazoan second messenger 2'3'-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2'3'-cGAMP signaling. In conclusion, our insights explain the tight control of STING signaling given varying background activation signals and provide a therapeutic hypothesis for autoimmune syndrome treatment.},
doi = {10.1016/j.cell.2019.05.036},
journal = {Cell},
number = 2,
volume = 178,
place = {United States},
year = {Thu Jun 20 00:00:00 EDT 2019},
month = {Thu Jun 20 00:00:00 EDT 2019}
}
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