ArticleProceedings of the National Academy of Sciences of the United States of America2022
ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 91 citations in OpenAlex.
- ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression.Cancer biology & therapy · 2026Article
- From initial complete response to recurrence: ENPP1 mutation drives cisplatin resistance through STING/NF-κB/IL-6 axis in hypopharyngeal squamous cell carcinoma.British journal of cancer · 2026Article
- SEVs-carried ENPP1 regulates DCs' activation and inhibits the formation of tertiary lymphoid structures in gastric cancer.Journal of gastroenterology · 2026Article
- STING: An Attractive Target for Autoimmune and Inflammatory Diseases.Medicinal research reviews · 2026Review
- Lymphocyte Micronucleus Formation Is Driven by Inflammation-Induced Oxidative DNA Damage in Oesophageal Cancer Development.International journal of cancer · 2026Article
- The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential.The Journal of clinical investigation · 2026Review
- An siENPP1-Delivering Bimetallic MOF Nanocomplex Enables Triple Activation of the cGAS-STING Pathway for Synergistic Triple-Negative Breast Cancer Therapy.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Molecular mechanisms regulating cGAS/STING activation in health and disease.The Journal of clinical investigation · 2026Review
- Viral capsid delivery of cGAMP enhances STING-dependent antitumor immune response.bioRxiv : the preprint server for biology · 2026Article
- Striking the right balance with type I interferon signalling in cancer.Nature reviews. Cancer · 2026Review
- A direct, real-time, spectrophotometric assay for measuring ENPP1-catalyzed cGAMP hydrolysis.The Journal of biological chemistry · 2026Article
- Alternative Polyadenylation Drives Runaway Pro-Inflammatory Macrophages in Periodontitis by Enabling Escape From miRNA Repression.Cell proliferation · 2026Article
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- The cGAS-STING pathway in cancer: friend or foe.Cell death & disease · 2026Review
- Cell-type specific activation of the cGAS-STING pathway in tumor immunotherapy: mechanisms and therapeutic implications.Journal of translational medicine · 2026Review
- The Emerging Role of Nanocarrier-Based Delivery Systems for cGAS-STING Activation in Cancer Immunotherapy.International journal of nanomedicine · 2026Review
- Bone marrow stromal cells enhance multiple myeloma cells proliferation through regulating LncRNA OVAAL/ENPP1 axis.Open life sciences · 2026Article
- The cGAS-STING pathway in pulmonary infectious and sterile inflammation: differences, connections, and therapeutic implications.Frontiers in immunology · 2026Review
- Research progress on the mechanisms of cGAS-STING signaling in immune cell infiltration associated with vascular remodeling.Journal of translational medicine · 2025Review
- Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The metazoan innate immune second messenger 2′3′-cGAMP is present both inside and outside cells. However, only extracellular cGAMP can be negatively regulated by the extracellular hydrolase ENPP1. Here, we determine whether ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating stimulator of interferon genes (STING) signaling. We identified ENPP1H362A, a point mutation that cannot degrade the 2′-5′ linkage in cGAMP while maintaining otherwise normal function. The selectivity of this histidine is conserved down to bacterial nucleotide pyrophosphatase/phosphodiesterase (NPP), allowing structural analysis and suggesting an unexplored ancient history of 2′-5′ cyclic dinucleotides. Enpp1H362A mice demonstrated that extracellular cGAMP is not responsible for the devastating phenotype in ENPP1-null humans and mice but is responsible for antiviral immunity and systemic inflammation. Our data define extracellular cGAMP as a pivotal STING activator, identify an evolutionarily critical role for ENPP1 in regulating inflammation, and suggest a therapeutic strategy for viral and inflammatory conditions by manipulating ENPP1 activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.