SESN1 alleviates autoimmunity by potentiating STING autophagic degradation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266409 | GEO | 2025/05/29
REPOSITORIES: GEO
Similar Datasets
Project description:SESN1 alleviates autoimmunity by potentiating STING autophagic degradation
| PRJNA1107113 | ENA
Project description:Stimulator of interferon genes (STING), the central hub protein of the cGAS-STING signaling, is essential for type I IFN production of innate immunity. However, prolonged or excessive activation of STING is highly related to autoimmune diseases, most of which exhibit the hallmark of elevated expression of type I interferons and IFN-stimulated genes (ISGs). Thus, the activity of STING must be stringently controlled to maintain immune homeostasis. Here, we reported that CK1α, a protein serine/threonine kinase, was essential to prevent the over-activation of STING-mediated type I IFN signaling through autophagic degradation of STING. Mechanistically, CK1α interacted with STING upon the cGAS-STING pathway activation and promoted STING autophagic degradation by enhancing the phosphorylation of p62 at serine 349, which was critical for p62 mediated STING autophagic degradation. Consistently, SSTC3, a selective CK1α agonist, significantly attenuated the response of the cGAS-STING signaling by promoting STING autophagic degradation. Importantly, pharmaceutical activation of CK1α using SSTC3 markedly repressed the systemic autoinflammatory responses in the Trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CK1α in the autophagic degradation of STING to maintain immune homeostasis. Manipulating CK1α through SSTC3 might be a potential therapeutic strategy for alleviating STING-mediated aberrant type I IFNs in autoimmune diseases.
2024-01-31 | GSE226593 | GEO
Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent findings indicate that STING can also function as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-11-30 | PXD058416 | Pride
Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-12-31 | GSE283415 | GEO
Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-12-31 | GSE283416 | GEO
Project description:We report positional cloning and characterization of a novel Sting allele that fails to activate IFN production in the wild-derived mice of MOLF/Ei strain in response to HSV (Herpes Simplex Virus) and Listeria monocytogenes both in vitro and in vivo. We show that previously uncharacterized mutations in the N-terminal of STING are responsible for low levels of IFN due to failure of MOLF STING to respond to cytosolic STING agonists such as 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or poly(deoxyadenylic-deoxythymidylic) acid (dAdT). Using Next-Generation Sequencing (NGS) for the analysis of DNA-responses in congenic C57BL6.StingMOLF/MOLF (MOLF STING) mouse macrophages, we show that these mutations in MOLF/Ei discriminate in responses between different STING agonists. Macrophages from C57BL6.StingB6/B6¬ (B6 STING), or B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. To examine differential gene regulation downstream of murine Tmem173 (STING) allelic variants. We stimulated macrophages from B6 mice congenic for MOLF STING; macrophages from B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. One replicate of RNA-seq reads after each stimulation provided. Conditions are peritoneal macrophages from B6 congenic mice expressing: B6 STING, MOLF STING, or STING KO stimulated with 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), poly(deoxyadenylic-deoxythymidylic) acid (dAdT), or no treatment. This constitutes a total of 12 reads analyzed in this data set.
2016-07-05 | E-GEOD-68140 | biostudies-arrayexpress
Project description:Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi?Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3?interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.
2017-11-06 | GSE106472 | GEO
Project description:Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi?Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3?interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.
2017-11-06 | GSE106471 | GEO
Project description:Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.
2022-06-23 | MSV000089711 | MassIVE
Project description:Gain-of-function mutations in STING1, that codes for the Stimulator of Interferon Gene (STING), result in a severe autoinflammatory disease termed STING-associated vasculopathy with onset in infancy (SAVI). Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, and their role in the onset and severity of SAVI remains to be elucidated. To address this point, we compared a single-cell RNA sequencing (scRNA-seq) dataset of peripheral blood mononuclear cells (PBMCs) from SAVI patients to a dataset of healthy PBMCs treated with recombinant IFN-β. We revealed a loss of mucosal associated invariant T cells and CD56bright natural killer cells in SAVI patients, not replicated in IFN-β-treated PBMC. Patient T cells are in an activated state associated with senescence and apoptosis, dependent on type I IFNs. Inferring cell to cell communication, from scRNA-seq predicted monocytes as potential drivers of this T cell phenotype and was supported by plasma cytokines measurement, with high CCL3, CCL4 and IL-6. Furthermore, scRNA-seq clustering identified a patient-specific subset of monocytes, highly inflammatory and expressing a strong integrated stress response (ISR). It also pinpointed to a patient with lower ISR, allowing us to identify a secondary mutation in PERK, that was recently shown to be activated by STING to trigger the ISR. Finally, based on the identification of this patient-specific subset of monocytes and the exploration of IFN-β stimulated PBMCs from healthy donors, we developed a strategy to propose a transcriptomic signature specific of STING activation and independent of type I IFN. Altogether, these results provide a deeper understanding of SAVI at the cellular and molecular levels.
2024-01-01 | GSE226598 | GEO