STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition

Ergun, Sabrina L.; Fernandez, Daniel; Weiss, Thomas M.; Li, Lingyin

doi:10.1016/j.cell.2019.05.036

Title: STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition

Journal Article · Thu Jun 20 00:00:00 EDT 2019 · Cell

DOI:https://doi.org/10.1016/j.cell.2019.05.036· OSTI ID:1546886

Ergun, Sabrina L. ^[1]; Fernandez, Daniel ^[1]; Weiss, Thomas M. ^[2]; Li, Lingyin ^[1]

Stanford Univ., CA (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515; P41GM103393; 5 T32 GM007276

OSTI ID:: 1546886

Journal Information:: Cell, Vol. 178, Issue 2; ISSN 0092-8674

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 132 works

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2′3′-cGAMP
innate immunity
STING associated vasculopathy with onset in infancy
SAVI
TMEM173
cyclic-di-GMPcyclic-di-AMP
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Title: STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition

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