5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

Prantner, Daniel; Perkins, Darren J.; Wei, Lai; Williams, Mark S.; Sharma, Shrutie; Fitzgerald, Katherine A.; Vogel, Stefanie N.

doi:10.1074/jbc.m112.382986

Cited by 182 publications

(157 citation statements)

References 83 publications

(73 reference statements)

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…Conversely, a different study demonstrated that phosphorylation of this same Ser-366 site plays a crucial role in activating STING-dependent signaling by facilitating binding of IRF3 to facilitate its phosphorylation by TBK1 (40). Previously, our lab identified mitochondrial membrane potential as a requirement for STING-mediated cytokine expression (22). This suggested the possibility that host mitochondria regulates STING, but our studies did not clarify the mechanism by which this may occur.…”

contrasting

confidence: 43%

“…Induction in Primary Macrophages-Innate signaling pathways can be regulated at many levels and we have shown previously that the cytokine response to the STING-activating ligand DMXAA is regulated by mitochondrial membrane potential, independent of ATP generation (22). In addition to cellular metabolism, host mitochondria also regulate calcium homeostasis (29), leading us to hypothesize that calcium concentrations alter the response to DMXAA.…”

Section: Inhibition Of Ampk Disrupts Sting-dependent Cytokinementioning

confidence: 99%

“…Primary peritoneal macrophages were isolated and cultured as previously described (22). Briefly, 4 days after i.p.…”

Section: Primary Macrophage Isolation and In Vitro Cell Culture-mentioning

confidence: 99%

“…A synthetic STING agonist, 5,6-dimethyl xanthenone-4-acetic acid (DMXAA), is a useful tool with which to study STING-dependent signaling because it is cell permeable and binds mouse, but not human, STING with rapid kinetics (20), leading to TBK1 activation, IRF3 phosphorylation, and subsequent cytokine induction (21) that is entirely STING-depen-dent (22). Thus, DMXAA mimics the effect of cGAMP in mouse cells.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

contrasting

confidence: 43%

Section: Inhibition Of Ampk Disrupts Sting-dependent Cytokinementioning

confidence: 99%

“…Primary peritoneal macrophages were isolated and cultured as previously described (22). Briefly, 4 days after i.p.…”

Section: Primary Macrophage Isolation and In Vitro Cell Culture-mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Preclinical exploration began with the agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which was recently demonstrated to directly interact with murine STING [103][104][105][106]. A single intratumoral dose of DMXAA in B16 melanoma-bearing mice was sufficient to promote rejection of most tumors, which was associated with a marked augmentation in the frequency of tumor antigen-specific CD8 + T cells.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

View full text Add to dashboard Cite

A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

show abstract

MnO₂ Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation‐Immunotherapy

Yang

Tang

et al. 2020

Advanced Science

View full text Add to dashboard Cite

MnO2 nanoparticles have been widely employed in cancer immunotherapy, playing a subsidiary role in assisting immunostimulatory drugs by improving their pharmacokinetics and/or creating a favorable microenvironment. Here, the stereotype of the subsidiary role of MnO2 nanoparticles in cancer immunotherapy is challenged. This study unravels an intrinsic immunomodulatory property of MnO2 nanoparticles as a unique nutrient‐responsive immunogenic cell death (ICD) inducer, capable of directly modulating immunosurveillance toward tumor cells. MnO2 nanoflowers (MNFs) constructed via a one pot self‐assembly approach selectively induce ICD to nutrient‐deprived but not nutrient‐replete cancer cells, which is confirmed by the upregulated damage associated molecular patterns in vitro and a prophylactic vaccination in vivo. The underlying mechanism of the MNFs‐mediated selective ICD induction is likely associated with the concurrently upregulated oxidative stress and autophagy. Built on their unique immunomodulatory properties, an innovative nanomaterials orchestrated cancer starvation‐immunotherapy is successfully developed, which is realized by the in situ vaccination with MNFs and vascular disrupting agents that cut off intratumoral nutrient supply, eliciting potent efficacy for suppressing local and distant tumors. These findings open up a new avenue toward biomedical applications of MnO2 materials, enabling an innovative therapeutics paradigm with great clinical significance.

show abstract

5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

Cited by 182 publications

References 83 publications

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

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

Innate immune signaling and regulation in cancer immunotherapy

MnO₂ Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation‐Immunotherapy

Contact Info

Product

Resources

About

5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

Cited by 182 publications

References 83 publications

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

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

Innate immune signaling and regulation in cancer immunotherapy

MnO2 Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation‐Immunotherapy

Contact Info

Product

Resources

About

MnO₂ Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation‐Immunotherapy