ArticleThe Journal of clinical investigation2022
An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 28 citations in OpenAlex.
- Innate immunity: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- The radiotherapy induced cyclic GMP-AMP-synthase re-localization and immune signature predicts HNSCC treatment efficacy.Communications medicine · 2026Article
- Precision targeting of STING: Challenges, innovations, and clinical outlook for cancer therapy.Innovation (Cambridge (Mass.)) · 2026Review
- Macromolecular Diamidobenzimidazole Conjugates Can Activate Stimulator of Interferon Genes.Journal of the American Chemical Society · 2025Article
- Andrographolide potentiates anti-tumor immunity in colorectal cancer (CRC) by targeting voltage-dependent anion channel (VDAC) and activating the cGAS-STING axis.Journal of gastrointestinal oncology · 2025Article
- Pattern recognition receptors: function, regulation and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- STING-ΔN, a novel splice isoform of STING, modulates innate immunity and autophagy in response to DNA virus infection.Cell communication and signaling : CCS · 2025Article
- Beyond survival to domination:Frontiers in microbiology · 2025Review
- Review
- Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.The Journal of clinical investigation · 2024Review
- The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies.Frontiers in pharmacology · 2024Review
- Extensive Alternative Splicing Patterns in Systemic Lupus Erythematosus Highlight Sexual Differences.Cells · 2023Article
- Immunomodulatory Gene-Splicing Dysregulation in Tumorigenesis: Unmasking the Complexity.Molecules (Basel, Switzerland) · 2023Review
- Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME.Journal of biomedical science · 2023Review
- Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway.Experimental & molecular medicine · 2023Review
- Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases.Zoological research · 2023Review
- cGAS-STING signaling pathway in intestinal homeostasis and diseases.Frontiers in immunology · 2023Review
- Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy.Signal transduction and targeted therapy · 2022Review
- Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes.Scientific reports · 2022Article
- Mitochondrial damage and activation of the cytosolic DNA sensor cGAS-STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice.Cell death discovery · 2022Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
It has been revealed that 2'3'-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of IFN genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identified as an importer to transport extracellular cGAMP into the cytosol. However, SLC19A1-deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, using immunoprecipitation, immunofluorescence, and flow cytometry, we identified an alternatively spliced STING isoform, plasmatic membrane STING (pmSTING), that localized in the plasma membrane with its C-terminus outside the cell, due to a lack of 1 transmembrane domain in its N-terminus compared with canonical STING. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and the production of IFN in pmSTING-transfected cells. Additionally, we also identified similar pmSTING isoforms in other species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into the role of cGAMP as an immunotransmitter.
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