STING is a direct innate immune sensor of cyclic di-GMP

被引:1284
作者
Burdette, Dara L. [1 ]
Monroe, Kathryn M. [1 ]
Sotelo-Troha, Katia [1 ]
Iwig, Jeff S. [1 ,2 ]
Eckert, Barbara [1 ]
Hyodo, Mamoru [3 ]
Hayakawa, Yoshihiro [4 ]
Vance, Russell E. [1 ]
机构
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Chem, Berkeley, CA 94720 USA
[3] Hokkaido Univ, Fac Pharmaceut Sci, Kita Ku, Sapporo, Hokkaido 0600812, Japan
[4] Aichi Inst Technol, Fac Engn, Dept Appl Chem, Toyota 4700392, Japan
基金
美国国家卫生研究院;
关键词
I INTERFERON RESPONSE; CYTOSOLIC DNA; PSEUDOMONAS-AERUGINOSA; INTRACELLULAR DNA; BIS-(3'-5')-CYCLIC-GMP; DIGUANYLATE; REVEALS; ADAPTER;
D O I
10.1038/nature10429
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
The innate immune system detects infection by using germline-encoded receptors that are specific for conserved microbial molecules. The recognition of microbial ligands leads to the production of cytokines, such as type I interferons (IFNs), that are essential for successful pathogen elimination. Cytosolic detection of pathogen-derived DNA is one major mechanism of inducing IFN production(1,2), and this process requires signalling through TANK binding kinase 1 (TBK1) and its downstream transcription factor, IFN-regulatory factor 3 (IRF3). In addition, a transmembrane protein called STING (stimulator of IFN genes; also known as MITA, ERIS, MPYS and TMEM173) functions as an essential signalling adaptor, linking the cytosolic detection of DNA to the TBK1-IRF3 signalling axis(3-7). Recently, unique nucleic acids called cyclic dinucleotides, which function as conserved signalling molecules in bacteria(8), have also been shown to induce a STING-dependent type I IFN response(9-12). However, a mammalian sensor of cyclic dinucleotides has not been identified. Here we report evidence that STING itself is an innate immune sensor of cyclic dinucleotides. We demonstrate that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and we show that unlabelled cyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di-GMP for binding to STING. Furthermore, we identify mutations in STING that selectively affect the response to cyclic dinucleotides without affecting the response to DNA. Thus, STING seems to function as a direct sensor of cyclic dinucleotides, in addition to its established role as a signalling adaptor in the IFN response to cytosolic DNA. Cyclic dinucleotides have shown promise as novel vaccine adjuvants and immunotherapeutics(9,13), and our results provide insight into the mechanism by which cyclic dinucleotides are sensed by the innate immune system.
引用
收藏
页码:515 / U111
页数:5
相关论文
共 26 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]   Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing [J].
Broz, Petr ;
von Moltke, Jakob ;
Jones, Jonathan W. ;
Vance, Russell E. ;
Monack, Denise M. .
CELL HOST & MICROBE, 2010, 8 (06) :471-483
[3]   The potential of 3′,5′-cyclic diguanylic acid (c-di-GMP) as an effective vaccine adjuvant [J].
Chen, Wangxue ;
KuoLee, Rhonda ;
Yan, Hongbin .
VACCINE, 2010, 28 (18) :3080-3085
[4]   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
[5]  
Chodosh L A, 2001, Curr Protoc Mol Biol, VChapter 12, DOI 10.1002/0471142727.mb1205s36
[6]   Phosphorylation-independent regulation of the diguanylate cyclase WspR [J].
De, Nabanita ;
Pirruccello, Michelle ;
Krasteva, Petya Violinova ;
Bae, Narae ;
Raghavan, Rahul Veera ;
Sondermann, Holger .
PLOS BIOLOGY, 2008, 6 (03) :601-617
[7]   An improved method for synthesizing cyclic bis(3′-5′)diguanylic acid (c-di-GMP) [J].
Hyodo, M ;
Hayakawa, Y .
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 2004, 77 (11) :2089-2093
[8]   A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA [J].
Ishii, KJ ;
Coban, C ;
Kato, H ;
Takahashi, K ;
Torii, Y ;
Takeshita, F ;
Ludwig, H ;
Sutter, G ;
Suzuki, K ;
Hemmi, H ;
Sato, S ;
Yamamoto, M ;
Uematsu, S ;
Kawai, T ;
Takeuchi, O ;
Akira, S .
NATURE IMMUNOLOGY, 2006, 7 (01) :40-48
[9]   STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling [J].
Ishikawa, Hiroki ;
Barber, Glen N. .
NATURE, 2008, 455 (7213) :674-U74
[10]   STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity [J].
Ishikawa, Hiroki ;
Ma, Zhe ;
Barber, Glen N. .
NATURE, 2009, 461 (7265) :788-U40