{"doi":"10.1126/sciadv.aba3688","title":"Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response","abstract":"Mechanisms linking immune sensing of DNA danger signals in the extracellular environment to innate pathways in the cytosol are poorly understood. Here, we identify a previously unidentified immune-metabolic axis by which cells respond to purine nucleosides and trigger a type I interferon-β (IFN-β) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dIno, or supplementation of dAdo or dIno stimulates IFN-β. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dIno. dIno is a functional immunometabolite that interferes with the cellular methionine cycle by inhibiting SAM synthetase activity. Inhibition of SAM-dependent transmethylation drives epigenomic hypomethylation and overexpression of immune-stimulatory endogenous retroviral elements that engage cytosolic dsRNA sensors and induce IFN-β. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA-derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-β production.","journal":"Science Advances","year":2020,"id":91829,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":6641,"name":"Mariko Takahashi","orcid":"0000-0003-2465-7907","position":1,"is_corresponding":false},{"id":239474,"name":"Ian T. Mathews","orcid":"0000-0003-4773-7985","position":2,"is_corresponding":false},{"id":459547,"name":"Camille Lenzi","orcid":"0000-0001-9659-2888","position":3,"is_corresponding":false},{"id":459548,"name":"Artem Romanov","orcid":"0000-0002-6771-6041","position":4,"is_corresponding":false},{"id":233458,"name":"Jeramie D. Watrous","orcid":"0000-0001-9124-6783","position":5,"is_corresponding":false},{"id":459549,"name":"Bartijn C. H. Pieters","orcid":"0000-0001-7171-3145","position":6,"is_corresponding":false},{"id":247023,"name":"Catherine C. Hedrick","orcid":"0000-0003-2045-4117","position":7,"is_corresponding":false},{"id":459550,"name":"Chris A. Benedict","orcid":"0000-0001-7816-656X","position":8,"is_corresponding":false},{"id":296413,"name":"Joel Linden","orcid":"0000-0001-7874-0090","position":9,"is_corresponding":false},{"id":376926,"name":"Roland Nilsson","orcid":"0000-0002-6020-7498","position":10,"is_corresponding":false},{"id":233460,"name":"Mohit Jain","orcid":"0000-0001-8628-2069","position":11,"is_corresponding":false},{"id":246517,"name":"Sonia Sharma","orcid":"0000-0002-6556-1963","position":12,"is_corresponding":false},{"id":230242,"name":"Rekha Dhanwani","orcid":"0000-0002-6592-8657","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T22:29:21.932251Z","pmid":"32743071","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}