Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING

Xu Zhang, Heping Shi, Jiaxi Wu, Xuewu Zhang, Lijun Sun, Chuo Chen, ZhijianJ Chen

Research output: Contribution to journalArticle

298 Citations (Scopus)

Abstract

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMPrevealed the structural basis of this high-affinitybinding and a ligand-induced conformational change in STING that may underlie its activation.

Original languageEnglish (US)
Pages (from-to)226-235
Number of pages10
JournalMolecular Cell
Volume51
Issue number2
DOIs
StatePublished - Jul 25 2013

Fingerprint

Ligands
GMP synthase (glutamine-hydrolyzing)
Adenosine Monophosphate
Phosphates
Guanosine Monophosphate
DNA
Second Messenger Systems
Innate Immunity
Cytoplasm
cyclic guanosine monophosphate-adenosine monophosphate
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING. / Zhang, Xu; Shi, Heping; Wu, Jiaxi; Zhang, Xuewu; Sun, Lijun; Chen, Chuo; Chen, ZhijianJ.

In: Molecular Cell, Vol. 51, No. 2, 25.07.2013, p. 226-235.

Research output: Contribution to journalArticle

@article{f44d7d6d17424f8686fc36052aa8d8f9,
title = "Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING",
abstract = "The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMPrevealed the structural basis of this high-affinitybinding and a ligand-induced conformational change in STING that may underlie its activation.",
author = "Xu Zhang and Heping Shi and Jiaxi Wu and Xuewu Zhang and Lijun Sun and Chuo Chen and ZhijianJ Chen",
year = "2013",
month = "7",
day = "25",
doi = "10.1016/j.molcel.2013.05.022",
language = "English (US)",
volume = "51",
pages = "226--235",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING

AU - Zhang, Xu

AU - Shi, Heping

AU - Wu, Jiaxi

AU - Zhang, Xuewu

AU - Sun, Lijun

AU - Chen, Chuo

AU - Chen, ZhijianJ

PY - 2013/7/25

Y1 - 2013/7/25

N2 - The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMPrevealed the structural basis of this high-affinitybinding and a ligand-induced conformational change in STING that may underlie its activation.

AB - The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMPrevealed the structural basis of this high-affinitybinding and a ligand-induced conformational change in STING that may underlie its activation.

UR - http://www.scopus.com/inward/record.url?scp=84880508067&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880508067&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2013.05.022

DO - 10.1016/j.molcel.2013.05.022

M3 - Article

VL - 51

SP - 226

EP - 235

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 2

ER -