TheN-Ethyl-N-Nitrosourea-InducedGoldenticketMouse Mutant Reveals an Essential Function ofStingin theIn VivoInterferon Response toListeria monocytogenesand Cyclic Dinucleotides

Sauer, John-Demian; Troha, Katia; Moltke, Jakob von; Monroe, Kathryn M.; Rae, Chris S.; Brubaker, Sky W.; Hyodo, Mamoru; Hayakawa, Yoshihiro; Woodward, Joshua J.; Portnoy, Daniel A.; Vance, Russell E.

doi:10.1128/iai.00999-10

Cited by 496 publications

(510 citation statements)

References 39 publications

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“…This response is dependent on the host cell helicase DDX41 59 , as well as the transmembrane receptor STING 60,61 . Both human and mouse cell lines depleted for DDX41 or STING as well as STING--knockout mice or mice harboring a loss of function mutation, no longer elicit a type I interferon response during infection with L. monocytogenes 59,60,62 . An interaction between STING and c--di--GMP has been reported in several studies 61, 63--66 .…”

Section: Other Cellular Processes Influenced By C--di--amp Levelsmentioning

confidence: 99%

Cyclic di-AMP: another second messenger enters the fray

2013

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Section: Other Cellular Processes Influenced By C--di--amp Levelsmentioning

confidence: 99%

Cyclic di-AMP: another second messenger enters the fray

2013

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“…Toll/IL-1R domain-containing adapter inducing IFN-b (Trif) 2/2 mice were obtained from Dr. S. Akira and backcrossed onto a C57BL/6J background (11 backcrosses) (26). Stimulator of IFN genes (STING) 2/2 (C57BL/6J-Tmem173 gt /J) (27) and CD11c-diphteria toxin receptor (DTR) (B6.FVB-Tg(Itgax-DTR/GFP)57Lan/J) (28) transgenic mice were obtained from The Jackson Laboratory. Animals were kept under specific pathogen-free conditions.…”

Section: Micementioning

confidence: 99%

Conventional but Not Plasmacytoid Dendritic Cells Foster the Systemic Virus–Induced Type I IFN Response Needed for Efficient CD8 T Cell Priming

Hervás-Stubbs

Riezu-Boj

Mancheño

et al. 2014

The Journal of Immunology

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Plasmacytoid dendritic cells (pDCs) are considered to be the principal type-I IFN (IFN-I) source in response to viruses, whereas the contribution of conventional DCs (cDCs) has been underestimated because, on a per-cell basis, they are not considered professional IFN-I–producing cells. We have investigated their respective roles in the IFN-I response required for CTL activation. Using a nonreplicative virus, baculovirus, we show that despite the high IFN-I–producing abilities of pDCs, in vivo cDCs but not pDCs are the pivotal IFN-I producers upon viral injection, as demonstrated by selective pDC or cDC depletion. The pathway involved in the virus-triggered IFN-I response is dependent on TLR9/MyD88 in pDCs and on stimulator of IFN genes (STING) in cDCs. Importantly, STING is the key molecule for the systemic baculovirus-induced IFN-I response required for CTL priming. The supremacy of cDCs over pDCs in fostering the IFN-I response required for CTL activation was also verified in the lymphocytic choriomeningitis virus model, in which IFN-β promoter stimulator 1 plays the role of STING. However, when the TLR-independent virus-triggered IFN-I production is impaired, the pDC-induced IFNs-I have a primary impact on CTL activation, as shown by the detrimental effect of pDC depletion and IFN-I signaling blockade on the residual lymphocytic choriomeningitis virus–triggered CTL response detected in IFN-β promoter stimulator 1−/− mice. Our findings reveal that cDCs play a major role in the TLR-independent virus-triggered IFN-I production required for CTL priming, whereas pDC-induced IFNs-I are dispensable but become relevant when the TLR-independent IFN-I response is impaired.

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“…This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is pivotal for IFN-␤ induction (17). Mouse STING-dependent signaling can also be triggered by the bacteria-specific metabolites cyclic di-AMP (8) and cyclic di-GMP (18), albeit with lesser potency than the endogenously produced cGAMP (16,19). Although the literature suggests that mouse STING is essential for up-regulation of IFN-␤ during a number of bacterial infections, it remains unclear whether this is through direct sensing of bacterial-derived dinucleotides or indirect means through cGAS-mediated production of cGAMP.…”

mentioning

confidence: 99%

“…STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7)(8)(9)(10)(11)(12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13)(14)(15).…”

mentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-␤ induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-␤ and TNF-␣ induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-␤ and TNF-␣ after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-␤ in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells.Pathogen sensing by innate immune cells is essential for host defense in response to invading microorganisms. Recognition by pattern recognition receptors typically activates signal transduction pathways, leading to up-regulation of cytokines like TNF-␣ and IFN-␤. Although IFN-␤ has a well established role in defense against viral infection, intracellular bacterial infections also induce this cytokine. In the past decade, our understanding of the molecular basis for these signaling pathways has expanded greatly and it has been discovered that there is some overlap between proteins responsible for recognition of bacteria and virus alike. One particular example is the mitochondrial and endoplasmic reticulum resident protein stimulator of interferon genes (STING) 2 (1-3). STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7-12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13-15). This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is piv...

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TheN-Ethyl-N-Nitrosourea-InducedGoldenticketMouse Mutant Reveals an Essential Function ofStingin theIn VivoInterferon Response toListeria monocytogenesand Cyclic Dinucleotides

Cited by 496 publications

References 39 publications

Cyclic di-AMP: another second messenger enters the fray

Cyclic di-AMP: another second messenger enters the fray

Conventional but Not Plasmacytoid Dendritic Cells Foster the Systemic Virus–Induced Type I IFN Response Needed for Efficient CD8 T Cell Priming

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

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