Open AccessJournal Article
DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response (P1375)
Kislay Parvatiyar,Zhiqiang Zhang,Rosane M. B. Teles,Songying Ouyang,Yan Jiang,Zhi-Jie Liu,Shankar S. Iyer,Shivam A. Zaver,Mirjam Schenk,Shang Zeng,Wenwan Zhong,Robert L. Modlin,Yongjun Liu,Genhong Cheng +13 more
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In this article, the authors identify the helicase, DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) as the pattern recognition receptor (PRR) that senses both cyclic-di-GMP and cyclic -di-AMP.Abstract:
Cytosolic detection of bacterially derived secondary messengers cyclic-di-GMP (c-di-GMP) or cyclic -di-AMP (c-di-AMP) by the host immune system activates an innate immune response characterized by the induction of type I interferons (IFNs) Induction of IFN by c-di-GMP or c-di-AMP has been shown to be dependent on a stimulator of IFN genes-TANK binding kinase 1-IFN regulatory factor 3 (STING-TBK1-IRF3) signaling axis Although STING has been shown to interact with c-di-GMP, an upstream sensor of these cyclic dinucleotides is unknown Here we identify the helicase, DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) as the pattern recognition receptor (PRR) that senses both c-di-GMP and c-di-AMP DDX41 specifically and directly interacts with c-di-GMP Knockdown of DDX41 via shRNA in murine or human immune cells inhibits the induction of innate immune genes and results in defective STING, TBK1 and IRF3 activation in response to c-di-GMP or c-di-AMP Our findings suggest a mechanism whereby c-di-GMP and c-di-AMP molecules are detected by the DDX41 PRR, which complexes with the STING adaptor to signal to TBK1-IRF3 and activate the IFN responseread more
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Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids
Jiaxi Wu,Zhijian J. Chen +1 more
TL;DR: Recent advances in understanding the mechanism of nucleic acid sensing and signaling in the cytosol of mammalian cells as well as the emerging role of cytosolic nucleic acids in autoimmunity are reviewed.
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DNA sensing by the cGAS–STING pathway in health and disease
TL;DR: The cGAS–STING pathway forms a major DNA-sensing mechanism in mammalian cells and emerging evidence of its role in monogenic inflammatory diseases and cancer and new therapeutic opportunities is highlighted.
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Bacterial type III secretion systems: specialized nanomachines for protein delivery into target cells
TL;DR: One of the most exciting developments in the field of bacterial pathogenesis in recent years is the discovery that many pathogens utilize complex nanomachines to deliver bacterially encoded effector proteins into target eukaryotic cells.
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Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid
Joseph E. Conlon,Dara Burdette,Shrutie Sharma,Numana Bhat,Mikayla R. Thompson,Zhaozhao Jiang,Vijay A. K. Rathinam,Brian G. Monks,Tengchuan Jin,T. Sam Xiao,Stefanie N. Vogel,Russell E. Vance,Katherine A. Fitzgerald +12 more
TL;DR: Stimulator of IFN gene (STING) is identified as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling, revealing an unexpected species-specific role for STING as a receptor for an anticancer drug.
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The interferon response to intracellular DNA: why so many receptors?
TL;DR: This review presents the evidence for the various interferon-inducing DNA receptors proposed to date, and examines the hypotheses that might explain why so many different receptors appear to be involved in the innate immune recognition of intracellular DNA.
References
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Journal ArticleDOI
STING is a direct innate immune sensor of cyclic di-GMP
Dara Burdette,Kathryn M. Monroe,Katia Sotelo-Troha,Jeffrey S. Iwig,Barbara Eckert,Mamoru Hyodo,Yoshihiro Hayakawa,Russell E. Vance +7 more
TL;DR: It is demonstrated that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and it is shown that unlabelledcyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di -GMP for binding to STING.
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The Adaptor Protein MITA Links Virus-Sensing Receptors to IRF3 Transcription Factor Activation
Bo Zhong,Yan Yang,Shu Li,Yan-Yi Wang,Ying Li,Feici Diao,Cao-Qi Lei,Xiao He,Lu Zhang,Po Tien,Hong-Bing Shu +10 more
TL;DR: The results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.
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STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling (Nature (2008) 455, (674-678))
Hiroki Ishikawa,Glen N. Barber +1 more
TL;DR: This corrects the article to show that the H2O2/H2O/O2 mixture is dominated by the H3O/ O2 mixture, rather than the O2/O3 mixture, which is more commonly associated with H2Os.
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STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
Yasuo Tanaka,Zhijian J. Chen +1 more
TL;DR: STING is shown to stimulate phosphorylation of IRF3 by the kinase TBK1 (TANK-binding kinase 1) in an in vitro reconstitution system, suggesting that STING functions as a scaffold protein to specify and promote the phosphorylated of IRf3 by TBk1.
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The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells
TL;DR: The identification of DDX41, a member of the DEXDc family of helicases, as an intracellular DNA sensor in myeloid dendritic cells (mDCs) is reported, suggesting thatDDX41 is an additional DNA sensor that depends on STING to sense pathogenic DNA.