{"gene":"OAS3","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2016,"finding":"OAS3 is the dominant OAS isoform responsible for RNase L activation during viral infection. CRISPR/Cas9 knockout of OAS3 (but not OAS1 or OAS2) in human A549 cells abolished 2-5A synthesis and RNase L-dependent rRNA degradation upon dsRNA transfection or infection with West Nile virus, Sindbis virus, influenza virus, or vaccinia virus. OAS3 displayed higher affinity for dsRNA in intact cells than OAS1 or OAS2.","method":"CRISPR-Cas9 knockout, 2-5A measurement, rRNA degradation assay, viral replication titration, dsRNA binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (KO, biochemical assays, viral replication), replicated across three human cell lines","pmids":["26858407"],"is_preprint":false},{"year":2008,"finding":"OAS3 exerts antiviral activity against Chikungunya virus by blocking early stages of viral RNA accumulation. A C-terminally truncated variant (OAS3-R844X) showed reduced antiviral activity, indicating the C-terminal ~20% of the protein is required for full antiviral function.","method":"Inducible stable expression of OAS3 or OAS3-R844X in HeLa cells, viral growth assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — clean overexpression system with truncation mutant, single lab","pmids":["19056102"],"is_preprint":false},{"year":2012,"finding":"OAS3 antiviral restriction of Chikungunya virus acts at the level of viral entry/early replication; a single amino acid change in the viral envelope glycoprotein E2 (E166K) confers resistance to OAS3-mediated restriction by enhancing viral entry efficiency.","method":"Luciferase reporter molecular clone, viral entry assay, site-directed mutagenesis of E2","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic entry assay with defined viral mutation, single lab","pmids":["22889614"],"is_preprint":false},{"year":2019,"finding":"In human macrophages, OAS3 (together with OAS1) negatively regulates RIG-I/MDA5-mediated induction of chemokines and interferon-stimulated genes, independently of type I interferon signaling itself. OAS3 KO cells showed increased chemokine and ISG expression upon intracellular poly(I:C) stimulation.","method":"CRISPR-Cas9 knockout, mRNA sequencing, cytokine measurement, pathway-specific stimulation","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with transcriptomic and functional readouts, single lab","pmids":["30078389"],"is_preprint":false},{"year":2019,"finding":"OAS3 (but not OAS1) is required for antiviral restriction of echovirus 7 mutants with elevated CpG or UpA dinucleotide frequencies, and OAS3/RNase L acts synergistically with ZAP in this restriction pathway.","method":"CRISPR-Cas9 knockout of OAS3 and RNase L, viral replication assays, replicon system","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — multiple KO cell lines with replicon and live virus, orthogonal pathway analysis","pmids":["31276592"],"is_preprint":false},{"year":2019,"finding":"In Egyptian Rousette bat RoNi/7 cells, RNase L activation and antiviral activity during Sindbis virus or vaccinia virus infection are dependent on OAS3 (not OAS1 or OAS2), and this activation is independent of MAVS signaling, indicating OAS3 acts as a direct pattern recognition receptor for viral dsRNA.","method":"CRISPR-Cas9 KO of OAS1, OAS2, OAS3, RNase L, MAVS; rRNA degradation assay; viral replication titration","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal KOs with functional readouts, replicates human cell findings in bat cells","pmids":["31719180"],"is_preprint":false},{"year":2022,"finding":"EV71 3C protease cleaves OAS3 at the Q982-G983 motif in the C-terminal region to escape antiviral restriction. Catalytically dead 3C mutants (H40G, E71A, C147G) and the rhinovirus 3C inhibitor rupintrivir abolished OAS3 cleavage and enhanced viral restriction.","method":"In vitro cleavage assay, site-directed mutagenesis of 3Cpro, protease inhibitor treatment, viral replication assays","journal":"Virologica Sinica","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage with mutagenesis defining exact cleavage site and catalytic residues","pmids":["35504537"],"is_preprint":false},{"year":2022,"finding":"OAS3 antiviral activity against EV71 requires its 2-5A synthesis catalytic activity; active-site mutations D816A, D818A, D888A, and K950A abolish EV71 restriction by preventing downstream RNase L activation. IFN-β1b-induced OAS3 expression is driven by STAT1 (not STAT3) phosphorylation binding directly to the OAS3 promoter.","method":"Active-site mutagenesis, RNase L activation assay, STAT1/3 knockdown, promoter binding assay, viral replication","journal":"Virologica Sinica","confidence":"High","confidence_rationale":"Tier 1 — catalytic mutagenesis defining active-site residues, with transcriptional regulation mechanistically defined","pmids":["35934228"],"is_preprint":false},{"year":2020,"finding":"DMRT3 binds OAS3 to form a complex with RNase L that promotes degradation of ESR1 mRNA. A disease-associated OAS3 R869H mutation reduces interaction of the DMRT3-OAS3 complex with ESR1 mRNA and RNase L, preventing ESR1 mRNA degradation and causing overexpression of ESR1.","method":"Co-immunoprecipitation, exome sequencing, in vitro RNA binding assay, patient testis tissue validation","journal":"Fertility and sterility","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and mRNA interaction assay with patient tissue validation, single lab","pmids":["32553473"],"is_preprint":false},{"year":2024,"finding":"IRF2 promotes basal expression of OAS3 in unstressed cells by binding to the OAS3 promoter, enabling rapid RNase L activation upon viral infection. IRF2 cooperates with STAT2 during interferon signaling to further enhance OAS3 expression. Loss of IRF2 impairs the initial wave of antiviral RNase L activation.","method":"Genome-wide CRISPR-Cas9 knockout screen (CRISPR-Translate), promoter binding assay, IRF2/STAT2 KO epistasis, RNase L activation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide screen with mechanistic follow-up including promoter binding and epistasis, multiple orthogonal methods","pmids":["39475651"],"is_preprint":false},{"year":2024,"finding":"TRIM21 E3 ligase mediates K48-linked polyubiquitination of OAS3 at K1079, targeting it for proteasomal degradation. Downregulation of TRIM21 in sepsis leads to OAS3 protein accumulation, which promotes epithelial cell apoptosis through RNase L activation.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K1079), proteasome inhibitor treatment, CLP mouse model, LPS cell model","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1-2 — defined ubiquitination site with mutagenesis, in vivo and in vitro validation, mechanistic pathway established","pmids":["39494334"],"is_preprint":false},{"year":2024,"finding":"HNRNPU restricts HBV transcription by positively regulating OAS3 expression, which then activates an RNase L-dependent innate immune response. HBx promotes HBx-DDB1-mediated degradation of HNRNPU, relieving OAS3-mediated restriction.","method":"HNRNPU knockdown/overexpression, OAS3 expression analysis, RNase L activation assay, HBV transcription measurement","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional knockdown/overexpression with defined pathway, single lab","pmids":["39011773"],"is_preprint":false},{"year":2019,"finding":"OAS1, OAS2, and OAS3 restrict intracellular Mycobacterium tuberculosis replication and enhance pro-inflammatory cytokine secretion (IL-1β, TNF-α, MCP-1). Silencing of these genes increased M. tb CFU counts and decreased cytokine levels.","method":"Gene silencing (siRNA), CFU counting, Luminex cytokine measurement","journal":"International journal of infectious diseases","confidence":"Low","confidence_rationale":"Tier 3 — siRNA knockdown with phenotypic readout but no molecular mechanism defined for OAS3 specifically","pmids":["30822544"],"is_preprint":false},{"year":2024,"finding":"OAS3 is upregulated in pancreatic cancer-associated M2d tumor-associated macrophages via a lactate/METTL3/OAS3 axis; METTL3-mediated m6A modification of OAS3 mRNA increases its expression. OAS3 deficiency in macrophages impairs IL-10 and VEGF-A secretion and M2d polarization.","method":"m6A modification analysis, METTL3 knockdown, OAS3 KO macrophages, cytokine measurement, humanized mouse models","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 — m6A modification with writer identified, functional KO with defined phenotypic output, in vivo validation","pmids":["39738657"],"is_preprint":false}],"current_model":"OAS3 is the dominant 2'-5'-oligoadenylate synthetase isoform in human cells that, upon binding viral dsRNA, synthesizes 2-5A to activate RNase L for antiviral RNA degradation; its expression is basally maintained by IRF2 (with STAT1/STAT2 amplification during interferon signaling), its protein stability is regulated by TRIM21-mediated K48-polyubiquitination at K1079, it can be inactivated by viral proteases (e.g., EV71 3Cpro cleavage at Q982-G983), and it also partners with DMRT3 to direct RNase L-mediated degradation of specific mRNAs such as ESR1."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that OAS3 restricts an alphavirus and that its C-terminal region is functionally required resolved that the largest OAS isoform possesses autonomous antiviral activity beyond a presumed redundancy with OAS1/OAS2.","evidence":"Inducible expression of OAS3 and truncation mutant OAS3-R844X in HeLa cells with Chikungunya virus replication assays","pmids":["19056102"],"confidence":"Medium","gaps":["Mechanism of early-stage restriction not defined","Catalytic activity of truncation mutant not measured directly"]},{"year":2012,"claim":"Demonstration that a single viral envelope mutation (E2-E166K) confers escape from OAS3 restriction by enhancing entry efficiency pinpointed the step at which OAS3 blocks Chikungunya virus.","evidence":"Luciferase reporter molecular clones, viral entry assays, and site-directed mutagenesis of E2 glycoprotein","pmids":["22889614"],"confidence":"Medium","gaps":["Whether OAS3/RNase L degrades incoming viral RNA at entry is not directly shown","Generalizability to other alphaviruses unknown"]},{"year":2016,"claim":"CRISPR knockout of individual OAS family members established OAS3 — not OAS1 or OAS2 — as the dominant isoform responsible for 2-5A synthesis and RNase L activation in human cells, fundamentally redefining the hierarchy within the OAS family.","evidence":"CRISPR-Cas9 KO of OAS1/2/3 in A549 and other human cell lines; 2-5A quantification, rRNA cleavage, and infection with WNV, Sindbis, influenza, and vaccinia","pmids":["26858407"],"confidence":"High","gaps":["Structural basis for OAS3's higher dsRNA affinity in cells not resolved","Whether OAS3 dominance holds in all human cell types is untested"]},{"year":2019,"claim":"Multiple studies expanded OAS3's functional scope: it synergizes with ZAP to restrict CpG/UpA-enriched viruses, it negatively regulates RIG-I/MDA5-dependent chemokine responses independently of type I IFN, and its dominance is conserved in bat cells acting independently of MAVS signaling.","evidence":"CRISPR KOs of OAS3, RNase L, ZAP, and MAVS in human A549 and bat RoNi/7 cells; echovirus replicon systems; transcriptomic and cytokine profiling in macrophages","pmids":["31276592","30078389","31719180"],"confidence":"High","gaps":["Molecular basis of OAS3-ZAP synergy undefined","How OAS3 cross-regulates RIG-I/MDA5 pathway mechanistically is unclear","Conservation of dominance across mammalian orders beyond bats and humans unknown"]},{"year":2020,"claim":"Discovery that OAS3 partners with DMRT3 to target ESR1 mRNA for RNase L-dependent degradation revealed a non-canonical, gene-specific mRNA decay role for the OAS3/RNase L axis beyond pan-antiviral defense.","evidence":"Co-immunoprecipitation, in vitro RNA binding assay, exome sequencing identifying OAS3 R869H, patient testis tissue validation","pmids":["32553473"],"confidence":"Medium","gaps":["How DMRT3-OAS3 selects specific mRNA targets is unknown","Whether the R869H variant affects canonical antiviral function is untested","Finding from single lab awaiting independent replication"]},{"year":2022,"claim":"Identification of EV71 3C protease cleavage of OAS3 at Q982-G983 and definition of catalytic residues D816/D818/D888/K950 as essential for 2-5A synthesis established the first viral immune evasion mechanism targeting OAS3 and mapped its enzymatic active site.","evidence":"In vitro cleavage assays with 3C catalytic-dead mutants, active-site mutagenesis of OAS3, STAT1 promoter binding analysis, viral replication assays","pmids":["35504537","35934228"],"confidence":"High","gaps":["Whether other viral proteases similarly cleave OAS3 is unexplored","No crystal structure of full-length OAS3 to confirm active-site architecture"]},{"year":2024,"claim":"A trio of discoveries resolved OAS3's transcriptional and post-translational regulation: IRF2 maintains basal OAS3 expression (cooperating with STAT2 under IFN), TRIM21 ubiquitinates K1079 for proteasomal turnover, and HNRNPU positively regulates OAS3 expression to restrict HBV.","evidence":"Genome-wide CRISPR screen with promoter binding and epistasis (IRF2/STAT2); ubiquitination assays with K1079 mutagenesis and CLP mouse model (TRIM21); HNRNPU knockdown/overexpression with HBV transcription measurement","pmids":["39475651","39494334","39011773"],"confidence":"High","gaps":["Full set of transcription factors regulating OAS3 not mapped","Whether TRIM21-OAS3 axis is exploited by specific viruses unknown","HNRNPU-OAS3 link tested only in single lab"]},{"year":2024,"claim":"Discovery that METTL3-mediated m6A modification of OAS3 mRNA upregulates its expression in tumor-associated macrophages, driving M2d polarization and cytokine secretion, extended OAS3's role to the tumor microenvironment.","evidence":"m6A modification analysis, METTL3 knockdown, OAS3 KO macrophages, cytokine measurement, humanized mouse model of pancreatic cancer","pmids":["39738657"],"confidence":"Medium","gaps":["Which m6A sites on OAS3 mRNA are functionally important is undefined","Whether the tumor-promoting effect requires OAS3 catalytic activity or is RNase L-independent is unknown"]},{"year":null,"claim":"No full-length OAS3 crystal or cryo-EM structure exists; the structural basis for its preferential dsRNA binding, allosteric activation across its three OAS domains, and selective mRNA targeting in partnership with DMRT3 remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of full-length OAS3","Mechanism of substrate selectivity in non-canonical mRNA decay unknown","In vivo physiological significance during natural human infection not established by genetic studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,4,7,8]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4,5,7,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,8]}],"complexes":[],"partners":["RNASEL","DMRT3","TRIM21","ZAP","IRF2","STAT1","STAT2"],"other_free_text":[]},"mechanistic_narrative":"OAS3 is the dominant 2'-5'-oligoadenylate synthetase isoform in human cells, functioning as a cytoplasmic pattern recognition receptor that senses viral double-stranded RNA and synthesizes 2-5A to activate the endoribonuclease RNase L for antiviral RNA degradation [PMID:26858407, PMID:31719180]. Its catalytic activity, mediated by active-site residues D816, D818, D888, and K950, is essential for antiviral restriction of diverse viruses including West Nile virus, Sindbis virus, influenza virus, Chikungunya virus, and enterovirus 71, and it cooperates with ZAP in restricting viruses with elevated CpG/UpA dinucleotide content [PMID:35934228, PMID:31276592, PMID:19056102]. Basal OAS3 transcription is maintained by IRF2 binding its promoter and amplified by STAT1/STAT2 during interferon signaling, while protein turnover is controlled by TRIM21-mediated K48-linked polyubiquitination at K1079, targeting OAS3 for proteasomal degradation; viral evasion strategies include direct proteolytic cleavage at Q982-G983 by the EV71 3C protease [PMID:39475651, PMID:39494334, PMID:35504537]. Beyond canonical antiviral defense, OAS3 partners with DMRT3 to direct RNase L-mediated degradation of specific mRNAs such as ESR1, and negatively regulates RIG-I/MDA5-dependent chemokine induction in macrophages [PMID:32553473, PMID:30078389]."},"prefetch_data":{"uniprot":{"accession":"Q9Y6K5","full_name":"2'-5'-oligoadenylate synthase 3","aliases":["p100 OAS","p100OAS"],"length_aa":1087,"mass_kda":121.2,"function":"Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes preferentially dimers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. Displays antiviral activity against Chikungunya virus (CHIKV), Dengue virus, Sindbis virus (SINV) and Semliki forest virus (SFV)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y6K5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OAS3","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OAS3","total_profiled":1310},"omim":[{"mim_id":"603351","title":"2-PRIME,5-PRIME-@OLIGOADENYLATE SYNTHETASE 3; OAS3","url":"https://www.omim.org/entry/603351"},{"mim_id":"603350","title":"2-PRIME,5-PRIME-@OLIGOADENYLATE SYNTHETASE 2; OAS2","url":"https://www.omim.org/entry/603350"},{"mim_id":"180435","title":"RIBONUCLEASE L; RNASEL","url":"https://www.omim.org/entry/180435"},{"mim_id":"164350","title":"2-PRIME,5-PRIME-@OLIGOADENYLATE SYNTHETASE 1; OAS1","url":"https://www.omim.org/entry/164350"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"salivary gland","ntpm":26.2}],"url":"https://www.proteinatlas.org/search/OAS3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6K5","domains":[{"cath_id":"3.30.460.10","chopping":"2-152","consensus_level":"medium","plddt":86.5056,"start":2,"end":152},{"cath_id":"3.30.460.10","chopping":"436-556_577-592","consensus_level":"medium","plddt":87.0256,"start":436,"end":592},{"cath_id":"1.10.1410.20","chopping":"595-618_625-731","consensus_level":"medium","plddt":91.4447,"start":595,"end":731},{"cath_id":"3.30.460.10","chopping":"747-895","consensus_level":"medium","plddt":90.6201,"start":747,"end":895}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6K5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6K5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6K5-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OAS3","jax_strain_url":"https://www.jax.org/strain/search?query=OAS3"},"sequence":{"accession":"Q9Y6K5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6K5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6K5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6K5"}},"corpus_meta":[{"pmid":"26858407","id":"PMC_26858407","title":"Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26858407","citation_count":232,"is_preprint":false},{"pmid":"19056102","id":"PMC_19056102","title":"The large form of human 2',5'-Oligoadenylate Synthetase (OAS3) exerts antiviral effect against Chikungunya virus.","date":"2008","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19056102","citation_count":83,"is_preprint":false},{"pmid":"31276592","id":"PMC_31276592","title":"The role of ZAP and OAS3/RNAseL pathways in the attenuation of an RNA virus with elevated frequencies of CpG and UpA dinucleotides.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31276592","citation_count":76,"is_preprint":false},{"pmid":"30822544","id":"PMC_30822544","title":"OAS1, OAS2 and OAS3 restrict intracellular M. tb replication and enhance cytokine secretion.","date":"2019","source":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30822544","citation_count":44,"is_preprint":false},{"pmid":"32321151","id":"PMC_32321151","title":"MALAT1 is involved in type I IFNs-mediated systemic lupus erythematosus by up-regulating OAS2, OAS3, and OASL.","date":"2020","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/32321151","citation_count":41,"is_preprint":false},{"pmid":"30078389","id":"PMC_30078389","title":"OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages.","date":"2019","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/30078389","citation_count":35,"is_preprint":false},{"pmid":"22889614","id":"PMC_22889614","title":"The E2-E166K substitution restores Chikungunya virus growth in OAS3 expressing cells by acting on viral entry.","date":"2012","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/22889614","citation_count":34,"is_preprint":false},{"pmid":"35305973","id":"PMC_35305973","title":"OAS1, OAS2, and OAS3 Contribute to Epidermal Keratinocyte Proliferation by Regulating Cell Cycle and Augmenting IFN-1‒Induced Jak1‒Signal Transducer and Activator of Transcription 1 Phosphorylation in Psoriasis.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35305973","citation_count":33,"is_preprint":false},{"pmid":"30207601","id":"PMC_30207601","title":"Alcohol Intake Interacts with CDKAL1, HHEX, and OAS3 Genetic Variants, Associated with the Risk of Type 2 Diabetes by Lowering Insulin Secretion in Korean Adults.","date":"2018","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/30207601","citation_count":26,"is_preprint":false},{"pmid":"31006500","id":"PMC_31006500","title":"Protein and fat intake interacts with the haplotype of PTPN11_rs11066325, RPH3A_rs886477, and OAS3_rs2072134 to modulate serum HDL concentrations in middle-aged people.","date":"2019","source":"Clinical nutrition (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/31006500","citation_count":22,"is_preprint":false},{"pmid":"35504537","id":"PMC_35504537","title":"EV71 3C protease cleaves host anti-viral factor OAS3 and enhances virus replication.","date":"2022","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/35504537","citation_count":18,"is_preprint":false},{"pmid":"31719180","id":"PMC_31719180","title":"Activation of RNase L in Egyptian Rousette Bat-Derived RoNi/7 Cells Is Dependent Primarily on OAS3 and Independent of MAVS 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39494334","citation_count":5,"is_preprint":false},{"pmid":"38752376","id":"PMC_38752376","title":"Bioinformatics approach combined with experimental verification reveals OAS3 gene implicated in paclitaxel resistance in head and neck cancer.","date":"2024","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/38752376","citation_count":5,"is_preprint":false},{"pmid":"36706688","id":"PMC_36706688","title":"Neuro-immune deconvolution analysis of OAS3 as a transcriptomic central node in HIV-associated neurocognitive disorders.","date":"2023","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36706688","citation_count":4,"is_preprint":false},{"pmid":"31618764","id":"PMC_31618764","title":"Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma.","date":"2019","source":"Investigative ophthalmology & visual 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selection","date":"2025-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.21.689732","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19195,"output_tokens":3321,"usd":0.0537},"stage2":{"model":"claude-opus-4-6","input_tokens":6710,"output_tokens":2588,"usd":0.147375},"total_usd":0.201075,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"OAS3 is the dominant OAS isoform responsible for RNase L activation during viral infection. CRISPR/Cas9 knockout of OAS3 (but not OAS1 or OAS2) in human A549 cells abolished 2-5A synthesis and RNase L-dependent rRNA degradation upon dsRNA transfection or infection with West Nile virus, Sindbis virus, influenza virus, or vaccinia virus. OAS3 displayed higher affinity for dsRNA in intact cells than OAS1 or OAS2.\",\n      \"method\": \"CRISPR-Cas9 knockout, 2-5A measurement, rRNA degradation assay, viral replication titration, dsRNA binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (KO, biochemical assays, viral replication), replicated across three human cell lines\",\n      \"pmids\": [\"26858407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OAS3 exerts antiviral activity against Chikungunya virus by blocking early stages of viral RNA accumulation. A C-terminally truncated variant (OAS3-R844X) showed reduced antiviral activity, indicating the C-terminal ~20% of the protein is required for full antiviral function.\",\n      \"method\": \"Inducible stable expression of OAS3 or OAS3-R844X in HeLa cells, viral growth assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression system with truncation mutant, single lab\",\n      \"pmids\": [\"19056102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OAS3 antiviral restriction of Chikungunya virus acts at the level of viral entry/early replication; a single amino acid change in the viral envelope glycoprotein E2 (E166K) confers resistance to OAS3-mediated restriction by enhancing viral entry efficiency.\",\n      \"method\": \"Luciferase reporter molecular clone, viral entry assay, site-directed mutagenesis of E2\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic entry assay with defined viral mutation, single lab\",\n      \"pmids\": [\"22889614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In human macrophages, OAS3 (together with OAS1) negatively regulates RIG-I/MDA5-mediated induction of chemokines and interferon-stimulated genes, independently of type I interferon signaling itself. OAS3 KO cells showed increased chemokine and ISG expression upon intracellular poly(I:C) stimulation.\",\n      \"method\": \"CRISPR-Cas9 knockout, mRNA sequencing, cytokine measurement, pathway-specific stimulation\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with transcriptomic and functional readouts, single lab\",\n      \"pmids\": [\"30078389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OAS3 (but not OAS1) is required for antiviral restriction of echovirus 7 mutants with elevated CpG or UpA dinucleotide frequencies, and OAS3/RNase L acts synergistically with ZAP in this restriction pathway.\",\n      \"method\": \"CRISPR-Cas9 knockout of OAS3 and RNase L, viral replication assays, replicon system\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO cell lines with replicon and live virus, orthogonal pathway analysis\",\n      \"pmids\": [\"31276592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Egyptian Rousette bat RoNi/7 cells, RNase L activation and antiviral activity during Sindbis virus or vaccinia virus infection are dependent on OAS3 (not OAS1 or OAS2), and this activation is independent of MAVS signaling, indicating OAS3 acts as a direct pattern recognition receptor for viral dsRNA.\",\n      \"method\": \"CRISPR-Cas9 KO of OAS1, OAS2, OAS3, RNase L, MAVS; rRNA degradation assay; viral replication titration\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal KOs with functional readouts, replicates human cell findings in bat cells\",\n      \"pmids\": [\"31719180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EV71 3C protease cleaves OAS3 at the Q982-G983 motif in the C-terminal region to escape antiviral restriction. Catalytically dead 3C mutants (H40G, E71A, C147G) and the rhinovirus 3C inhibitor rupintrivir abolished OAS3 cleavage and enhanced viral restriction.\",\n      \"method\": \"In vitro cleavage assay, site-directed mutagenesis of 3Cpro, protease inhibitor treatment, viral replication assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage with mutagenesis defining exact cleavage site and catalytic residues\",\n      \"pmids\": [\"35504537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OAS3 antiviral activity against EV71 requires its 2-5A synthesis catalytic activity; active-site mutations D816A, D818A, D888A, and K950A abolish EV71 restriction by preventing downstream RNase L activation. IFN-β1b-induced OAS3 expression is driven by STAT1 (not STAT3) phosphorylation binding directly to the OAS3 promoter.\",\n      \"method\": \"Active-site mutagenesis, RNase L activation assay, STAT1/3 knockdown, promoter binding assay, viral replication\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — catalytic mutagenesis defining active-site residues, with transcriptional regulation mechanistically defined\",\n      \"pmids\": [\"35934228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DMRT3 binds OAS3 to form a complex with RNase L that promotes degradation of ESR1 mRNA. A disease-associated OAS3 R869H mutation reduces interaction of the DMRT3-OAS3 complex with ESR1 mRNA and RNase L, preventing ESR1 mRNA degradation and causing overexpression of ESR1.\",\n      \"method\": \"Co-immunoprecipitation, exome sequencing, in vitro RNA binding assay, patient testis tissue validation\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and mRNA interaction assay with patient tissue validation, single lab\",\n      \"pmids\": [\"32553473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF2 promotes basal expression of OAS3 in unstressed cells by binding to the OAS3 promoter, enabling rapid RNase L activation upon viral infection. IRF2 cooperates with STAT2 during interferon signaling to further enhance OAS3 expression. Loss of IRF2 impairs the initial wave of antiviral RNase L activation.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen (CRISPR-Translate), promoter binding assay, IRF2/STAT2 KO epistasis, RNase L activation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide screen with mechanistic follow-up including promoter binding and epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"39475651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM21 E3 ligase mediates K48-linked polyubiquitination of OAS3 at K1079, targeting it for proteasomal degradation. Downregulation of TRIM21 in sepsis leads to OAS3 protein accumulation, which promotes epithelial cell apoptosis through RNase L activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K1079), proteasome inhibitor treatment, CLP mouse model, LPS cell model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — defined ubiquitination site with mutagenesis, in vivo and in vitro validation, mechanistic pathway established\",\n      \"pmids\": [\"39494334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPU restricts HBV transcription by positively regulating OAS3 expression, which then activates an RNase L-dependent innate immune response. HBx promotes HBx-DDB1-mediated degradation of HNRNPU, relieving OAS3-mediated restriction.\",\n      \"method\": \"HNRNPU knockdown/overexpression, OAS3 expression analysis, RNase L activation assay, HBV transcription measurement\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional knockdown/overexpression with defined pathway, single lab\",\n      \"pmids\": [\"39011773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OAS1, OAS2, and OAS3 restrict intracellular Mycobacterium tuberculosis replication and enhance pro-inflammatory cytokine secretion (IL-1β, TNF-α, MCP-1). Silencing of these genes increased M. tb CFU counts and decreased cytokine levels.\",\n      \"method\": \"Gene silencing (siRNA), CFU counting, Luminex cytokine measurement\",\n      \"journal\": \"International journal of infectious diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with phenotypic readout but no molecular mechanism defined for OAS3 specifically\",\n      \"pmids\": [\"30822544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OAS3 is upregulated in pancreatic cancer-associated M2d tumor-associated macrophages via a lactate/METTL3/OAS3 axis; METTL3-mediated m6A modification of OAS3 mRNA increases its expression. OAS3 deficiency in macrophages impairs IL-10 and VEGF-A secretion and M2d polarization.\",\n      \"method\": \"m6A modification analysis, METTL3 knockdown, OAS3 KO macrophages, cytokine measurement, humanized mouse models\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A modification with writer identified, functional KO with defined phenotypic output, in vivo validation\",\n      \"pmids\": [\"39738657\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OAS3 is the dominant 2'-5'-oligoadenylate synthetase isoform in human cells that, upon binding viral dsRNA, synthesizes 2-5A to activate RNase L for antiviral RNA degradation; its expression is basally maintained by IRF2 (with STAT1/STAT2 amplification during interferon signaling), its protein stability is regulated by TRIM21-mediated K48-polyubiquitination at K1079, it can be inactivated by viral proteases (e.g., EV71 3Cpro cleavage at Q982-G983), and it also partners with DMRT3 to direct RNase L-mediated degradation of specific mRNAs such as ESR1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OAS3 is the dominant 2'-5'-oligoadenylate synthetase isoform in human cells, functioning as a cytoplasmic pattern recognition receptor that senses viral double-stranded RNA and synthesizes 2-5A to activate the endoribonuclease RNase L for antiviral RNA degradation [PMID:26858407, PMID:31719180]. Its catalytic activity, mediated by active-site residues D816, D818, D888, and K950, is essential for antiviral restriction of diverse viruses including West Nile virus, Sindbis virus, influenza virus, Chikungunya virus, and enterovirus 71, and it cooperates with ZAP in restricting viruses with elevated CpG/UpA dinucleotide content [PMID:35934228, PMID:31276592, PMID:19056102]. Basal OAS3 transcription is maintained by IRF2 binding its promoter and amplified by STAT1/STAT2 during interferon signaling, while protein turnover is controlled by TRIM21-mediated K48-linked polyubiquitination at K1079, targeting OAS3 for proteasomal degradation; viral evasion strategies include direct proteolytic cleavage at Q982-G983 by the EV71 3C protease [PMID:39475651, PMID:39494334, PMID:35504537]. Beyond canonical antiviral defense, OAS3 partners with DMRT3 to direct RNase L-mediated degradation of specific mRNAs such as ESR1, and negatively regulates RIG-I/MDA5-dependent chemokine induction in macrophages [PMID:32553473, PMID:30078389].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that OAS3 restricts an alphavirus and that its C-terminal region is functionally required resolved that the largest OAS isoform possesses autonomous antiviral activity beyond a presumed redundancy with OAS1/OAS2.\",\n      \"evidence\": \"Inducible expression of OAS3 and truncation mutant OAS3-R844X in HeLa cells with Chikungunya virus replication assays\",\n      \"pmids\": [\"19056102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of early-stage restriction not defined\", \"Catalytic activity of truncation mutant not measured directly\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that a single viral envelope mutation (E2-E166K) confers escape from OAS3 restriction by enhancing entry efficiency pinpointed the step at which OAS3 blocks Chikungunya virus.\",\n      \"evidence\": \"Luciferase reporter molecular clones, viral entry assays, and site-directed mutagenesis of E2 glycoprotein\",\n      \"pmids\": [\"22889614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OAS3/RNase L degrades incoming viral RNA at entry is not directly shown\", \"Generalizability to other alphaviruses unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CRISPR knockout of individual OAS family members established OAS3 — not OAS1 or OAS2 — as the dominant isoform responsible for 2-5A synthesis and RNase L activation in human cells, fundamentally redefining the hierarchy within the OAS family.\",\n      \"evidence\": \"CRISPR-Cas9 KO of OAS1/2/3 in A549 and other human cell lines; 2-5A quantification, rRNA cleavage, and infection with WNV, Sindbis, influenza, and vaccinia\",\n      \"pmids\": [\"26858407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for OAS3's higher dsRNA affinity in cells not resolved\", \"Whether OAS3 dominance holds in all human cell types is untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple studies expanded OAS3's functional scope: it synergizes with ZAP to restrict CpG/UpA-enriched viruses, it negatively regulates RIG-I/MDA5-dependent chemokine responses independently of type I IFN, and its dominance is conserved in bat cells acting independently of MAVS signaling.\",\n      \"evidence\": \"CRISPR KOs of OAS3, RNase L, ZAP, and MAVS in human A549 and bat RoNi/7 cells; echovirus replicon systems; transcriptomic and cytokine profiling in macrophages\",\n      \"pmids\": [\"31276592\", \"30078389\", \"31719180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of OAS3-ZAP synergy undefined\", \"How OAS3 cross-regulates RIG-I/MDA5 pathway mechanistically is unclear\", \"Conservation of dominance across mammalian orders beyond bats and humans unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that OAS3 partners with DMRT3 to target ESR1 mRNA for RNase L-dependent degradation revealed a non-canonical, gene-specific mRNA decay role for the OAS3/RNase L axis beyond pan-antiviral defense.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro RNA binding assay, exome sequencing identifying OAS3 R869H, patient testis tissue validation\",\n      \"pmids\": [\"32553473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DMRT3-OAS3 selects specific mRNA targets is unknown\", \"Whether the R869H variant affects canonical antiviral function is untested\", \"Finding from single lab awaiting independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of EV71 3C protease cleavage of OAS3 at Q982-G983 and definition of catalytic residues D816/D818/D888/K950 as essential for 2-5A synthesis established the first viral immune evasion mechanism targeting OAS3 and mapped its enzymatic active site.\",\n      \"evidence\": \"In vitro cleavage assays with 3C catalytic-dead mutants, active-site mutagenesis of OAS3, STAT1 promoter binding analysis, viral replication assays\",\n      \"pmids\": [\"35504537\", \"35934228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other viral proteases similarly cleave OAS3 is unexplored\", \"No crystal structure of full-length OAS3 to confirm active-site architecture\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A trio of discoveries resolved OAS3's transcriptional and post-translational regulation: IRF2 maintains basal OAS3 expression (cooperating with STAT2 under IFN), TRIM21 ubiquitinates K1079 for proteasomal turnover, and HNRNPU positively regulates OAS3 expression to restrict HBV.\",\n      \"evidence\": \"Genome-wide CRISPR screen with promoter binding and epistasis (IRF2/STAT2); ubiquitination assays with K1079 mutagenesis and CLP mouse model (TRIM21); HNRNPU knockdown/overexpression with HBV transcription measurement\",\n      \"pmids\": [\"39475651\", \"39494334\", \"39011773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of transcription factors regulating OAS3 not mapped\", \"Whether TRIM21-OAS3 axis is exploited by specific viruses unknown\", \"HNRNPU-OAS3 link tested only in single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that METTL3-mediated m6A modification of OAS3 mRNA upregulates its expression in tumor-associated macrophages, driving M2d polarization and cytokine secretion, extended OAS3's role to the tumor microenvironment.\",\n      \"evidence\": \"m6A modification analysis, METTL3 knockdown, OAS3 KO macrophages, cytokine measurement, humanized mouse model of pancreatic cancer\",\n      \"pmids\": [\"39738657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which m6A sites on OAS3 mRNA are functionally important is undefined\", \"Whether the tumor-promoting effect requires OAS3 catalytic activity or is RNase L-independent is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No full-length OAS3 crystal or cryo-EM structure exists; the structural basis for its preferential dsRNA binding, allosteric activation across its three OAS domains, and selective mRNA targeting in partnership with DMRT3 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of full-length OAS3\", \"Mechanism of substrate selectivity in non-canonical mRNA decay unknown\", \"In vivo physiological significance during natural human infection not established by genetic studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 4, 7, 8]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNASEL\", \"DMRT3\", \"TRIM21\", \"ZAP\", \"IRF2\", \"STAT1\", \"STAT2\"],\n    \"other_free_text\": []\n  }\n}\n```"}