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bioRxiv · 10.1101/552166

STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition

Ergun, S. L.·Fernandez, D.·Weiss, T. M.·Li, L.
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Abstract

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 23-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 23-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a novel therapeutic hypothesis for autoimmune syndrome treatment.

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Ergun, S. L., Fernandez, D., Weiss, T. M., Li, L.. 2019-02-15. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. https://doi.org/10.1101/552166

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