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

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 e...

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Podrobná bibliografie
Vydáno v:	Cell Ročník 178; číslo 2; s. 290
Hlavní autoři:	Ergun, Sabrina L, Fernandez, Daniel, Weiss, Thomas M, Li, Lingyin
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 11.07.2019
Témata:	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 cGAMP innate immunity STING associated vasculopathy with onset in infancy SAVI STING cyclic-di-GMP TMEM173 2′3′-cGAMP cyclic-di-AMP cyclic-dinucleotide
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2019.05.036