Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA

The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infe...

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Published in:Annual review of biochemistry Vol. 86; p. 541
Main Authors: Kato, Kazuki, Omura, Hiroki, Ishitani, Ryuichiro, Nureki, Osamu
Format: Journal Article
Language:English
Published: United States 20.06.2017
Subjects:
Animals
Bacteria
Crystallography, X-Ray
Cytosol - chemistry
Cytosol - immunology
DNA - chemistry
DNA - genetics
DNA - immunology
Gene Expression Regulation
Humans
Immunity, Innate
Interferon Regulatory Factor-3 - chemistry
Interferon Regulatory Factor-3 - genetics
Interferon Regulatory Factor-3 - immunology
Models, Molecular
Nucleotides, Cyclic - chemistry
Nucleotides, Cyclic - genetics
Nucleotides, Cyclic - immunology
Nucleotidyltransferases - chemistry
Nucleotidyltransferases - genetics
Nucleotidyltransferases - immunology
Phosphorylation
Protein Conformation
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - immunology
Second Messenger Systems - genetics
Second Messenger Systems - immunology
type I interferon
cGAS
STING
cGAMP
innate immune system
ISSN:1545-4509, 1545-4509
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Summary:The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclic GMP-AMP (2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3). Numerous crystal structures of the components of this cGAS/STING signaling axis have been reported and these clarify the structural basis for their signal transduction mechanisms. In this review, we summarize recent progress made in the structural dissection of this signaling pathway and indicate possible directions of forthcoming research.
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ISSN:1545-4509
1545-4509
DOI:10.1146/annurev-biochem-061516-044813