STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease

Dobbs, Nicole; Burnaevskiy, Nikolay; Chen, Didi; Gonugunta, Vijaya Kumar; Alto, Neal M.; Yan, Nan

doi:10.1016/j.chom.2015.07.001

Cited by 475 publications

(449 citation statements)

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“…We recently showed that pharmacological inhibition of TBK1 ameliorates disease phenotypes in Trex1 −/− mice (21). STING activation involves trafficking from the ER to cytoplasmic vesicles through the secretory pathway (13), during which time TBK1 is recruited and travels with STING as part of the STING signalsome, which is potentially targeted to lysosomes for degradation to prevent excessive IFN response (22) (see the model in Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

“…A previous study found that TBK1 interacts with mTORC1 and inhibits its activity in prostate cancer cells (12). In the case of DNA sensing, STING recruits TBK1 to form the "STING signalsome" as soon as it exits the ER, and both proteins travel through the secretory pathway, potentially reaching lysosomes where mTORC1 is located (13). To test this possibility, we first knocked down TBK1 in WT and Trex1 −/− cells using four independent siRNAs.…”

Section: Significancementioning

confidence: 99%

“…To confirm the mitochondrial defect and pinpoint the specific step(s) of cellular metabolism that might be affected by Trex1 −/− , we performed 13 C isotope tracing to determine the fate of glucose-derived carbon (11). After culturing with [U- 13 C]glucose, the unlabeled fraction of citrate (m+0) was significantly increased in Trex1 −/− cells compared with WT, whereas the fraction of labeled citrate arising from 13 C entry into and progression around the TCA cycle (m+2, m+4, and m+5) was significantly decreased (Fig. 1 H and I).…”

Section: Significancementioning

confidence: 99%

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Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Three-prime repair exonuclease 1 knockout (Trex1 −/− ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANKbinding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 −/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 −/− background, and many metabolic defects persist in Trex1 −/− Irf3 −/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 −/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 −/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.M ammals have evolved complex and integrated systems of immunity and metabolism to maintain and defend internal and environmental threats. Increasing numbers of immune regulators have been found to play critical roles in metabolism. Studies from recent years have established an integrated view on the shared architecture between adaptive immunity and metabolism, including how they correspond to stimulus in disease settings. However, cell-intrinsic innate immune regulation of metabolic pathways remains poorly understood. This is in part due to the fact that overwhelming systemic inflammation in chronic diseases often masks direct underlying molecular causes.We have previously characterized an autoimmune/autoinflammatory disease mouse model, three-prime repair exonuclease 1 knockout (Trex1 −/− ) (1). TREX1, also known as DNase III, is an exonuclease that localizes to the endoplasmic reticulum (ER) to prevent aberrant accumulation of self-DNA or glycans that would trigger immune activation (2, 3). Mutations of the TREX1 gene have been associated with several autoinflammatory and autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) (4). Trex1 −/− mice suffer from systemic inflammation caused largely by chronic activation of the cytosolic DNA sensing pathway through the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) cascade (5-7). We showed previously that TREX1 also regulates lysosomal biogenesis through the mTORC1-TFEB pathway and that Trex1 −/− mouse embryonic fibroblasts (MEFs) exhibit drastically reduced mTORC1 activity compare...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of the regulated trafficking of signaling molecules is underscored by the findings that Shigella inhibits STING signaling by blocking its translocation from the ER to ERGIC and that the ERGIC/Golgi trafficking mechanism of STING is deregulated in genetic autoinflammatory diseases (14). Our work demonstrates that the transport of BTN3A1-mediated TBK1 to the perinuclear region is critical for the induction of IFN-β gene expression in response to nucleic acid stimulation.…”

Section: Discussionmentioning

confidence: 78%

“…STING-mediated TBK1/IRF3 is fully activated at the ER-Golgi intermediate compartment (ERGIC) (14). STING, TBK1, and IRF3, all essential components for inducing type I IFN signaling, have been shown to translocate to these punctate structures, although the mechanism responsible for the dynamic trafficking of such molecules is unknown.…”

mentioning

confidence: 99%

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

Seo

Lee

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA-and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid-or virus-triggered activation of IFN-β production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1-TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubuleassociated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA-or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling.BTN3A1 | type I IFN signaling | TBK1-IRF3 axis | MAP4 | dynein

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Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

Luo

Shu

2017

FEBS Letters

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Edited by Wilhelm JustRhomboid-like pseudoproteases are a conserved superfamily of proteins related to the rhomboid intramembrane serine proteases that lack key catalytic residues. iRhom2, a member of the rhomboid-like pseudoprotease superfamily, regulates the maturation and trafficking of ADAM17 and is associated with inflammatory arthritis. Recent studies demonstrate that iRhom2 is also involved in innate immunity by regulating the trafficking and stability of MITA (also called STING), which is a central adaptor in innate antiviral signalling pathways. Here, we summarize recent progress on the roles and mechanisms of iRhom2 and its homologues in innate immunity and also discuss the links between the physiological functions of iRhoms and immunological diseases.

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STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease

Cited by 475 publications

References 28 publications

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

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