Cell
Volume 178, Issue 2, 11 July 2019, Pages 290-301.e10
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Article
STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition

https://doi.org/10.1016/j.cell.2019.05.036Get rights and content
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Highlights

  • cGAMP binding to STING causes C-terminal tail release and polymerization

  • Disease-causing STING mutant R284S is unable to sequester STING C-terminal tail

  • Ligand-activated STING polymer is disulfide bridge stabilized at C148

  • Bacterial ligand CDG is a partial inhibitor of cGAMP-mediated STING signaling

Summary

How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, 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. Our insights explain the tight control of STING signaling given varying background activation signals and provide a therapeutic hypothesis for autoimmune syndrome treatment.

Keywords

STING
cGAMP
2′3′-cGAMP
innate immunity
STING associated vasculopathy with onset in infancy
SAVI
TMEM173
cyclic-di-GMP
cyclic-di-AMP
cyclic-dinucleotide

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