IRE1α Downregulation Enhances STING-Mediated Chemoresistance and Guides Precision Therapies in Pancreatic Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE284365 | GEO | 2025/09/03
REPOSITORIES: GEO
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Project description:IRE1α Downregulation Enhances STING-Mediated Chemoresistance and Guides Precision Therapies in Pancreatic Cancer
| PRJNA1198885 | ENA
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.
2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
2014-05-31 | E-GEOD-57604 | biostudies-arrayexpress
Project description:STING is an intracellular sensor of cyclic di-nucleotides involved in response to pathogen- or self-derived DNA that induces protective immunity, or if dysregulated, autoimmunity. STING trafficking is tightly linked to its activity. We aimed to systematically characterize genes regulating STING trafficking and to define their impact on STING responses. Based on proximity-ligation proteomics and genetic screens, an ESCRT complex containing HGS, VPS37A and UBAP1 was found to be required for STING degradation and signaling shutdown. Oligomerization-driven STING ubiquitination by UBE2N formed a platform for ESCRT recruitment at the endosome, responsible for STING signaling shutdown. A UBAP1 mutant that underlies human spastic paraplegia and disrupts ESCRT function led to STING-dependent type I IFN responses at the steady-state, defining ESCRT as a homeostatic regulator of STING signaling.
2022-12-14 | MSV000090900 | MassIVE
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, the pivotal adaptor protein of CGAS-STING signaling, is critical for type I IFN production of innate immunity. However, excessive or prolonged activation of STING is associated with autoinflammatory and autoimmune diseases. Thus, preventing STING from over-activation is important to maintain immune homeostasis. Here, we reported that SESN1 was essential to prevent the excessive activation of STING-mediated type I IFN signaling through autophagic degradation of STING.
2025-05-29 | GSE266409 | GEO
Project description:The STING signaling pathway plays important roles in many cancers, viral and bacterial infections, and autoimmune diseases. Understanding how STING mediates expression of many proteins in the host and bacterial cells can provide important clues about the biochemical processes, opening the door for the development of new therapies. Using STING KO cells, we were able to identify many differentially expressed proteins between the wild type and STING KO RAW macrophage. We identified proteins that were exclusively detected only in the wild type or only in the STING KO, as well as those that were comply identified but showed different levels of expressions between the two cell lines. This included several proteins that are known as potent biomarkers of various cancers and autoimmune diseases. Our data broaden the knowledge of proteins that are related to STING signaling, and may have identified novel proteins that have therapeutic value. This will require rigorous validation in the future studies. Many protein biomarkers can be regulated by post-translational modifications and protein-protein interactions. While beyond the scope of the current study, we note that methods are available at the Purdue Proteomics Facility for mapping post-translational modifications and protein-protein interactions. We envision this to be an exciting line of enquiry for us in the future.
2019-07-03 | MSV000084058 | MassIVE
Project description:<p>The Krebs cycle-derived metabolite itaconate, whose production is catalyzed by immune response gene 1 (IRG1), has excellent potential to link immunity and metabolism in activated macrophages through alkylation or competitive inhibition of target proteins. In support of this, our previous study demonstrated that the stimulator of interferon genes (STING) signaling platform functions as a hub in macrophage immunity and has a profound impact on the prognosis of sepsis. Interestingly, we found that itaconate, an endogenous immunomodulator, can significantly inhibit the activation of STING signaling. Moreover, 4-octyl itaconate (4-OI), which is a permeable itaconate derivative, could alkylate cysteine sites 65, 71, 88, and 147 of STING, thereby inhibiting its phosphorylation and downregulating the production of related inflammatory factors. Furthermore, itaconate and 4-OI inhibited the production of inflammatory factors in sepsis models. Our results have broadened the role of the IRG1-Itaconate axis in immunomodulation and highlighted itaconate and its derivatives as potential therapeutic agents in sepsis.</p>
2023-01-15 | MTBLS5877 | MetaboLights
Project description:STING-mediated activation of TAK1 at the ER, which in turn induces STING phosphorylation and initiates STEEP-mediated STING trafficking. These findings shed light on an early signaling event in the regulation of STING exit from ER.
2023-09-05 | PXD045096 |
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