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

Cell. 2019 Jul 11;178(2):290-301.e10. doi: 10.1016/j.cell.2019.05.036. Epub 2019 Jun 20.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / metabolism
  • Dimerization
  • Endoplasmic Reticulum / metabolism
  • HEK293 Cells
  • Humans
  • Ligands
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Nucleotides, Cyclic / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Signal Transduction


  • Ligands
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Recombinant Proteins
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP