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

被引：1918

作者：

Wu, Jiaxi ^{[1
]}

Sun, Lijun ^{[1
,2
]}

Chen, Xiang ^{[1
]}

Du, Fenghe ^{[1
]}

Shi, Heping ^{[3
]}

Chen, Chuo ^{[3
]}

Chen, Zhijian J. ^{[1
,2
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

来源：

SCIENCE | 2013年 / 339卷 / 6121期

关键词：

D O I：

10.1126/science.1229963

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-beta. Thus, cGAMP in metazoans and functions as an endogenous second messenger that triggers interferon production in response to cytosolic DNA.

引用

页码：826 / 830

页数：5

共 17 条

[1] RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate [J].

Ablasser, Andrea ;

Bauernfeind, Franz ;

Hartmann, Gunther ;

Latz, Eicke ;

Fitzgerald, Katherine A. ;

Hornung, Veit .

NATURE IMMUNOLOGY, 2009, 10 (10) :1065-U40

[2] Nucleic Acid Recognition by the Innate Immune System [J].

Barbalat, Roman ;

Ewald, Sarah E. ;

Mouchess, Maria L. ;

Barton, Gregory M. .

ANNUAL REVIEW OF IMMUNOLOGY, VOL 29, 2011, 29 :185-214

[3] Cytoplasmic DNA innate immune pathways [J].

Barber, Glen N. .

IMMUNOLOGICAL REVIEWS, 2011, 243 :99-108

[4] EARL SUTHERLAND (1915-1975) AND THE DISCOVERY OF CYCLIC AMP [J].

Blumenthal, Stanley A. .

PERSPECTIVES IN BIOLOGY AND MEDICINE, 2012, 55 (02) :236-249

[5] STING is a direct innate immune sensor of cyclic di-GMP [J].

Burdette, Dara L. ;

Monroe, Kathryn M. ;

Sotelo-Troha, Katia ;

Iwig, Jeff S. ;

Eckert, Barbara ;

Hyodo, Mamoru ;

Hayakawa, Yoshihiro ;

Vance, Russell E. .

NATURE, 2011, 478 (7370) :515-U111

[6] The prokaryote messenger c-di-GMP triggers stalk cell differentiation in Dictyostelium [J].

Chen, Zhi-hui ;

Schaap, Pauline .

NATURE, 2012, 488 (7413) :680-683

[7] RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway [J].

Chiu, Yu-Hsin ;

MacMillan, John B. ;

Chen, Zhijian J. .

CELL, 2009, 138 (03) :576-591

[8] Coordinated Regulation of Accessory Genetic Elements Produces Cyclic Di-Nucleotides for V. cholerae Virulence [J].

Davies, Bryan W. ;

Bogard, Ryan W. ;

Young, Travis S. ;

Mekalanos, John J. .

CELL, 2012, 149 (02) :358-370

[9] Herpes simplex virus ICP0 and ICP34.5 counteract distinct interferon-induced barriers to virus replication [J].

Mossman, KL ;

Smiley, JR .

JOURNAL OF VIROLOGY, 2002, 76 (04) :1995-1998

[10] Bacterial nucleotide-based second messengers [J].

Pesavento, Christina ;

Hengge, Regine .

CURRENT OPINION IN MICROBIOLOGY, 2009, 12 (02) :170-176

← 1 2 →