The structural basis for the sensing and binding of cyclic di-GMP by STING

Huang, Yongyang; Liu, Xiangyu; Du, Xiaoxia; Jiang, Zhengfan; Su, Xiao‐Dong

doi:10.1038/nsmb.2333

Cited by 183 publications

(176 citation statements)

References 21 publications

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“…3A). This observation is consistent with the fact that the dimerization of MITA is mediated by the domains comprising the aa segments 153-173 or 155-180 (38)(39)(40). Additionally, MRP and MITA were coimmunoprecipitated with RIG-I, VISA, IKKi, and IRF3 (Fig.…”

Section: Mrp Blocks the Interaction Of Mita And Tbk1supporting

confidence: 73%

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Chen

Pei

Zhu

et al. 2014

The Journal of Immunology

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Mediator of IFN regulatory transcription factor 3 activation (MITA) is an important adaptor protein to mediate the induction of type I IFNs. In this study, we identified an alternatively spliced isoform of MITA lacking exon 7, termed MITA-related protein (MRP). MRP shares the N-terminal portion aa 1–253 with MITA but possesses a unique 30-aa sequence at the carboxyl terminal part, therefore lacking the conserved domains including TANK-binding kinase 1 (TBK1) and cyclic diguanylate binding domain. MRP is expressed in multiple tissues and distinct cell lines. Overexpression of MRP inhibited MITA-mediated activation of IFN-β promoter by sendai virus infection and cyclic diguanylate treatment but enhanced that in HSV-1 infection. Interestingly, MRP expression was reduced after Sendai virus infection but was upregulated after HSV-1 infection. Overexpression of MRP inhibited MITA-mediated induction of IFN-β via TBK1-IFN regulatory transcription factor 3 by disrupting the MITA-TBK1 interaction. However, NF-κB pathway was still activated by MRP, as MRP retained the ability to interact with inducible inhibitor of NF-κB (iκB) kinase. Thus, MRP acts as a dominant negative regulator of MITA-mediated induction of IFN production.

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Section: Mrp Blocks the Interaction Of Mita And Tbk1supporting

confidence: 73%

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Chen

Pei

Zhu

et al. 2014

The Journal of Immunology

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“…STING binds c-di-GMP with a K D of 5 M and stimulates production of type I interferons by signaling through the TANK binding kinase 1 (TBK1) and the interferon regulatory transcription factor 3 (IRF3) (69). At least five groups have solved the crystal structure of STING (70,72,73,177,421) in complex with c-di-GMP (Fig. 5G).…”

Section: Cyclic Di-gmp As An Immunomodulatormentioning

confidence: 99%

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Römling

Galperin

Gomelsky

2013

Microbiol Mol Biol Rev

1,468

1,698

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SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.

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“…However, the DNA sensor involved in recognizing infection by adenovirus leading to early IRF3 activation has not been convincingly established. The recent identification of cyclic dinucleotide activation of STING (14)(15)(16)(17)(18) and the elegant discovery of cyclic-GMP-AMP synthase (cGAS) as a DNA sensor (19,20) provide an important bridge between DNA detection and downstream signaling. cGAS in complex with duplex DNA (21)(22)(23) leads to enzyme activation and production of a novel cyclic guanine-adenine dinucleotide (cGAMP) (24)(25)(26)(27) and STING activation.…”

mentioning

confidence: 99%

Adenovirus Detection by the cGAS/STING/TBK1 DNA Sensing Cascade

Lam

Stein

Falck-Pedersen

2014

J Virol

198

149

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T he human serotype 5 adenovirus (Ad5) is a nonenveloped linear double-stranded DNA virus associated with upper respiratory tract disease in humans. It has been extensively studied as a model for virus and host cell interactions. Replication-defective recombinant Ad5 vectors (rAdV) deleted in E1 and E3 coding domains have been characterized in gene therapy, vaccine, and oncolytic vector strategies in the murine model. Although nonpermissive for Ad5 replication, the murine model of rAdV infection provides a valuable resource for characterizing how the innate and adaptive immune response orchestrates an antiviral response to nonenveloped DNA viruses.Virus uptake by immune sentinel cells such as macrophage and dendritic cells is vital to initiating the antiviral immune response. In addition to antigen-presenting cells (APCs), other cell types, including endothelial cells or tissue-specific cells such as hepatocytes, when exposed to virus, also contribute to the host antiviral response. In vitro studies of isolated bone marrow-derived APCs or representative cell lines have revealed a cell-specific antiviral innate response, where activation of the type I interferon (IFN) cascade is a dominant feature (1-4). A valuable marker for early events in the antiviral recognition response is activation of the transcription factor interferon response factor 3 (IRF3). Following infection, cytosolic IRF3 undergoes phosphorylation as a primary response to adenovirus uptake. Activation occurs in a MyD88/TRIF-independent manner; it requires integrin-dependent endosomal entry, escape, and presentation of viral DNA to the cytosolic compartment (3).In rAdV-responsive murine cell lines, the STING/TBK1 cascade is required for IRF3 phosphorylation (5, 6). STING (7,8) functions as an adaptor linking DNA recognition signaling to activation of the TBK1 kinase. TBK1 activation (9) leads to C-terminal IRF3 phosphorylation, dimerization, and translocation to the nucleus (10, 11). In the nucleus, IRF3, in collaboration with additional transcription factors (NF-B and AP1), results in transcriptional activation of IRF3-responsive genes (including IFN-␤) (12). This sequence of events contributes to the primary antiviral response to adenovirus infection. The translation of primary response transcripts such as IFN-␤ leads to autocrine/paracrine secondary signaling. The combination of primary and secondary response functions leads to expression of a complete antiviral response, which is distinct for different cell types.Using various screening protocols, cell lines, and output assays, an extensive list of cytosolic DNA sensors, including DAI, RNA polymerase (Pol) III, IFI16, DDX41, and Aim 2, has been established (reviewed in reference 13). However, the DNA sensor involved in recognizing infection by adenovirus leading to early IRF3 activation has not been convincingly established. The recent identification of cyclic dinucleotide activation of STING (14-18) and the elegant discovery of cyclic-GMP-AMP synthase (cGAS) as a DNA sensor (19,20) provide an...

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The structural basis for the sensing and binding of cyclic di-GMP by STING

Cited by 183 publications

References 21 publications

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Adenovirus Detection by the cGAS/STING/TBK1 DNA Sensing Cascade

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