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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| Vydáno v: | Annual review of biochemistry Ročník 86; s. 541 |
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| Hlavní autoři: | , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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20.06.2017
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| ISSN: | 1545-4509, 1545-4509 |
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| Abstract | 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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| AbstractList | 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.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. 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. |
| Author | Kato, Kazuki Omura, Hiroki Ishitani, Ryuichiro Nureki, Osamu |
| Author_xml | – sequence: 1 givenname: Kazuki surname: Kato fullname: Kato, Kazuki email: ishitani@bs.u-tokyo.ac.jp, nureki@bs.u-tokyo.ac.jp organization: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp – sequence: 2 givenname: Hiroki surname: Omura fullname: Omura, Hiroki email: ishitani@bs.u-tokyo.ac.jp, nureki@bs.u-tokyo.ac.jp organization: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp – sequence: 3 givenname: Ryuichiro surname: Ishitani fullname: Ishitani, Ryuichiro email: ishitani@bs.u-tokyo.ac.jp, nureki@bs.u-tokyo.ac.jp organization: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp – sequence: 4 givenname: Osamu surname: Nureki fullname: Nureki, Osamu email: ishitani@bs.u-tokyo.ac.jp, nureki@bs.u-tokyo.ac.jp organization: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28399655$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA |
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