{"gene":"OASL","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"OASL (p59OASL) was identified as a novel OAS family member with a conserved N-terminal OAS-like domain but lacking 2'-5' oligoadenylate synthetase activity; its C-terminus contains two ubiquitin-like domains, distinguishing it from other OAS family members.","method":"cDNA cloning, genomic sequencing, sequence/domain analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — full-length cDNA characterization and domain analysis in single study; lack of enzymatic activity established by sequence inference, not yet by direct in vitro assay","pmids":["9722630"],"is_preprint":false},{"year":2004,"finding":"OASL (p59OASL) interacts with the transcriptional repressor MBD1 (methyl CpG-binding protein 1) via its C-terminal ubiquitin-like domain; the interaction was confirmed by yeast two-hybrid, in vitro pulldown, and in vivo co-immunoprecipitation, and was specific (OASL did not interact with other MBD family members, and MBD1 did not interact with OAS1).","method":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vitro pulldown and yeast two-hybrid, single lab, multiple orthogonal methods","pmids":["14728690"],"is_preprint":false},{"year":2009,"finding":"OASL gene induction by viral infection is rapid and mediated by IRF-3 (IFN regulatory factor 3), independently of a functional type I IFN response, in contrast to OAS1 which requires type I IFN signaling for its induction.","method":"Gene expression analysis during Sendai virus and Influenza A virus infection; IRF-3 pathway dissection","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by functional dissection (IRF-3-dependent vs IFN-dependent induction), single lab","pmids":["19203244"],"is_preprint":false},{"year":2012,"finding":"A splice variant of human OASL (OASL d), derived by deletion of exons 4 and 5 and retaining the ubiquitin-like domain, exhibits antiviral activity against RNA viruses (EV71, VSV) but not HSV-2; OASL b, which lacks the ubiquitin-like domain but shares the N-terminus, has no antiviral activity, implicating the ubiquitin-like domain in antiviral function.","method":"RT-PCR cloning, ectopic expression, viral infection assays, immunoblotting","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain dissection using natural splice variants with gain-of-function experiments, single lab","pmids":["22531715"],"is_preprint":false},{"year":2013,"finding":"Mouse OASL1 negatively regulates type I IFN production; OASL1 deficiency leads to sustained type I IFN levels (primarily from plasmacytoid dendritic cells) during chronic LCMV infection, accelerated viral clearance, and restored CD8+ T-cell function, demonstrating OASL1 as a negative regulator of the innate antiviral response.","method":"Oasl1 knockout mice, LCMV chronic infection model, serum cytokine measurements, flow cytometry, viral titer assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse model with multiple defined cellular and molecular phenotypes, independently replicated in subsequent studies","pmids":["23874199"],"is_preprint":false},{"year":2014,"finding":"Human OASL enhances RIG-I activation by mimicking K63-linked polyubiquitin through its C-terminal ubiquitin-like domain; OASL interacts and colocalizes with RIG-I, and its expression suppresses replication of multiple RNA viruses in a RIG-I-dependent manner; loss of OASL reduces RIG-I signaling and enhances virus replication. Mouse Oasl2 is the functionally equivalent ortholog.","method":"Co-immunoprecipitation, colocalization imaging, RIG-I-dependent rescue experiments, loss-of-function (siRNA knockdown), gain-of-function (overexpression), Oasl2 KO bone-marrow-derived macrophages, multi-virus replication assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, colocalization, domain-specific mechanism (UBL mimicking polyubiquitin), RIG-I epistasis, KO mouse cells, multiple orthogonal methods, replicated in subsequent studies","pmids":["24931123"],"is_preprint":false},{"year":2015,"finding":"The OAS-like domain of human OASL adopts a crystal structure resembling activated OAS1 and contains a positively charged dsRNA binding groove; OASL binds dsRNA through this domain, and mutation of key residues in the dsRNA binding site abolishes the ability of OASL to enhance RIG-I signaling, demonstrating that dsRNA binding is essential for OASL's co-activator function.","method":"X-ray crystallography, dsRNA binding assays, site-directed mutagenesis, RIG-I signaling reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assay; multiple orthogonal methods in one study establishing mechanism","pmids":["25925578"],"is_preprint":false},{"year":2018,"finding":"Mouse OASL1 forms stress granules that trap viral RNAs during early viral infection, promoting efficient RLR (RIG-I-like receptor) signaling; this stress granule formation depends on the RNA binding activity of OASL1. In late stages of infection, OASL1 interacts with IRF7 mRNA transcripts to inhibit IRF7 translation, thereby downregulating type I IFN production.","method":"Subcellular localization imaging, stress granule assays, viral RNA trapping experiments, RNA-binding assays, IRF7 translation assays","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (stress granule formation linked to RLR signaling enhancement), and IRF7 mRNA interaction, single lab","pmids":["29463066"],"is_preprint":false},{"year":2019,"finding":"Human OASL and mouse Oasl2 directly bind cGAS (independently of dsDNA) and inhibit cGAS enzymatic activity (cyclic GMP-AMP production) via non-competitive inhibition, thereby suppressing type I IFN induction during DNA virus infection; OASL-deficient cells and Oasl2-/- mice show increased IFN production and reduced DNA virus (vaccinia, HSV, adenovirus) replication, and cGAS is required for this phenotype.","method":"Co-immunoprecipitation, cGAS enzymatic activity assays, OASL-deficient human cells and Oasl2 KO mice, multi-virus replication assays, genetic epistasis (cGAS knockdown rescue)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding demonstrated by Co-IP, enzymatic inhibition assayed in vitro, genetic epistasis with cGAS, KO mouse model, multiple viruses; replicated by subsequent studies","pmids":["30635239"],"is_preprint":false},{"year":2018,"finding":"Tupaia OASL1 (tree shrew ortholog) associates with mitochondria and directly interacts with both MDA5 and MAVS via its OAS and UBL domains; upon RNA virus infection, tOASL1 enhances MDA5-MAVS interaction to potentiate type I IFN signaling.","method":"Co-immunoprecipitation, subcellular fractionation/localization, overexpression and knockdown assays, IFN signaling reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing direct interaction with MDA5 and MAVS, localization data, gain/loss-of-function, single lab","pmids":["33188074"],"is_preprint":false},{"year":2022,"finding":"OASL1/OASL regulates eNOS (NOS3) mRNA stability in endothelial cells; endothelial Oasl1 deficiency leads to reduced eNOS expression through PI3K/Akt-dependent upregulation of miR-584 (a negative regulator of NOS3 mRNA), resulting in impaired NO bioavailability and accelerated atherosclerotic plaque progression. miR-584 inhibition rescues the effects of OASL knockdown.","method":"Endothelial-specific Oasl1 knockout mice, atherosclerosis model, miRNA inhibitor rescue experiments, PI3K/Akt pathway inhibition, mRNA stability assays, Western blot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO mouse model, mechanistic pathway dissection (PI3K/Akt → OASL → miR-584 → NOS3 mRNA), rescue experiments, multiple orthogonal methods","pmids":["36333342"],"is_preprint":false},{"year":2022,"finding":"Mouse OASL1 acts downstream of NRF2 in macrophages; OASL1 deficiency enhances G3BP1- and TBK1-mediated inflammatory responses and induces apoptosis/necroptosis via APAF1/cytochrome c/caspase-9 and RIPK3 pathways during hepatic ischemia-reperfusion injury.","method":"Myeloid-specific TXNIP KO mice, NRF2 disruption experiments, OASL1 deficiency experiments, pathway analysis (STING/TBK1, apoptosis/necroptosis markers), histological and biochemical assays","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model placing OASL1 downstream of NRF2 and upstream of TBK1/G3BP1 and apoptotic machinery, single lab, multiple pathway readouts","pmids":["36035360"],"is_preprint":false},{"year":2023,"finding":"OASL promotes virus-induced necroptosis by undergoing liquid-like phase condensation, which scaffolds the RIPK3-ZBP1 necrosome complex; OASL phase-separated droplets recruit RIPK3 and ZBP1 via protein-protein interactions, providing spatial segregation that facilitates RIPK3 amyloid-like fibril formation, autophosphorylation, and subsequent MLKL phosphorylation. Oasl1-deficient mice show severely impaired necroptosis and succumb to uncontrolled viral infection.","method":"Phase condensation assays, co-immunoprecipitation, RIPK3 fibril/amyloid assays, MLKL phosphorylation assays, Oasl1 KO mouse viral infection model, live cell imaging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (phase condensation, Co-IP, fibril assays, phosphorylation, KO mouse), mechanistic pathway established with in vitro and in vivo validation","pmids":["36604592"],"is_preprint":false},{"year":2023,"finding":"OASL1 negatively regulates IRF7 translation (not transcription), thereby reducing type I IFN production; mouse Oasl1 KO leads to increased IRF7 protein and enhanced type I IFN in response to tumors, promoting antitumor immunity with increased CD8+ T cells, NK cells, and CD8α+ DCs in tumors.","method":"Oasl1 KO mice, syngeneic tumor transplant models, IRF7 protein measurement, flow cytometry, IFN-I measurement","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined molecular mechanism (IRF7 protein level increase), multiple cellular phenotypes, single lab","pmids":["27034232"],"is_preprint":false},{"year":2023,"finding":"OASL knockdown in stomach adenocarcinoma cells suppresses mTORC1 signaling (reduced p-mTOR and p-RPS6KB1), inhibiting cell proliferation, migration, and invasion; OASL overexpression activates mTORC1 signaling, and rapamycin reverses OASL overexpression-induced tumor cell growth, establishing OASL as an upstream activator of mTORC1 in STAD.","method":"siRNA knockdown, overexpression, mTOR/RPS6KB1 phosphorylation Western blot, rapamycin rescue, xenograft tumor formation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue placing OASL upstream of mTORC1, single lab","pmids":["36809539"],"is_preprint":false},{"year":2023,"finding":"Rare OASL variants (R60W, T261S, A447V, 202Q) found in SLE patients enhance type I IFN secretion by dendritic cells differentiated from patient-derived iPSCs; genome editing of the 202Q variant to wild-type 202R reduced IFN secretion, and introduction of 202Q into wild-type iPSCs enhanced it, confirming functional causality.","method":"Patient-derived iPSC differentiation to DCs, CRISPR/Cas9 genome editing, IFN secretion assays","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic genome editing with bidirectional functional consequence, patient-derived cells, single lab","pmids":["37354689"],"is_preprint":false},{"year":2024,"finding":"OASL interacts with viral protein VP2 of IBDV (infectious bursal disease virus) and targets it for degradation via the autophagy receptor p62/SQSTM1 through the autophagy pathway; lysine 316 of VP2 is the critical site for this autophagy-mediated degradation, and K316R mutation abolishes VP2 degradation and enhances IBDV replication.","method":"Co-immunoprecipitation, overexpression/knockdown assays, autophagy pathway assays, site-directed mutagenesis (VP2 K316R), viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis identifying critical residue, autophagy pathway validation, single lab","pmids":["38639485"],"is_preprint":false},{"year":2024,"finding":"Pi16 (peptidase inhibitor 16) binds to OASL by co-immunoprecipitation and promotes pancreatic ductal adenocarcinoma cell proliferation via OASL; functional rescue experiments confirmed that Pi16's proliferative effect depends on OASL.","method":"Co-immunoprecipitation, CRISPR/Cas9 knockout of Pi16, functional rescue with OASL, in vitro and in vivo proliferation assays","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction, functional rescue, single lab, limited mechanistic detail on how OASL mediates proliferation","pmids":["38353288"],"is_preprint":false},{"year":2025,"finding":"OASL promotes immune evasion in pancreatic ductal adenocarcinoma by enhancing NBR1-mediated autophagy-lysosomal degradation of MHC-I; OASL knockdown restores total and surface MHC-I levels, increases CD8+ T-cell infiltration, and slows tumor growth in vivo.","method":"Co-immunoprecipitation, flow cytometry, Western blot, immunofluorescence, orthotopic PDAC mouse model, OASL knockdown","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying OASL-NBR1-MHC-I pathway, in vivo and in vitro validation, multiple methods, single lab","pmids":["39990208"],"is_preprint":false},{"year":2025,"finding":"OASL promotes mTOR-independent and MAPK (p38)-dependent keratinocyte hyperproliferation and inflammatory/lipid metabolic dysregulation in psoriasis; OASL expression is regulated by the JAK1-STAT1 axis (Upadacitinib inhibits STAT1 and reduces OASL), and OASL knockdown suppresses p38 MAPK activation.","method":"OASL knockdown and overexpression in HaCaT cells, JAK1 inhibitor treatment, p38 MAPK pathway analysis, imiquimod-induced psoriasis mouse model","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain/loss-of-function placing OASL in JAK1-STAT1 axis upstream of p38 MAPK, single lab, limited mechanistic detail","pmids":["40360089"],"is_preprint":false},{"year":2025,"finding":"OASL directly binds cGAS (confirmed by Co-IP and immunofluorescence) and inhibits cGAMP generation, reducing STING-mediated antitumor immunity and sustaining matrix stiffness in hepatocellular carcinoma; OASL knockdown activates cGAS-STING signaling and promotes M1 macrophage polarization, and STING inhibitor C-176 reverses these effects.","method":"Co-immunoprecipitation, immunofluorescence, ELISA (cGAMP), Western blot, flow cytometry, subcutaneous HCC mouse model, STING inhibitor rescue","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct OASL-cGAS binding confirmed by Co-IP and immunofluorescence, enzymatic inhibition (cGAMP), genetic epistasis with STING inhibitor, in vivo validation, single lab","pmids":["41330170"],"is_preprint":false},{"year":2025,"finding":"Intrinsic (pre-infection) expression of OASL is essential for robust type III IFN (IFNL) induction during influenza A virus infection; single-cell RNA-seq analysis of temporal infection data identified OASL as a correlate of IFN induction potential, and validation experiments confirmed OASL as necessary for this heterogeneous cellular IFN response.","method":"Temporal single-cell RNA sequencing, OASL knockdown/loss-of-function validation, IAV infection model, IFNL induction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq discovery validated by loss-of-function experiments establishing OASL as necessary for IFNL induction, single lab","pmids":["41468430"],"is_preprint":false},{"year":2026,"finding":"OASL interacts with the ZBP1-PANoptosome complex via co-immunoprecipitation; TRAF1 transcriptionally activates OASL, and OASL promotes PANoptosis (combined apoptosis/necroptosis/pyroptosis) during H. pylori infection of gastric epithelial cells; OASL overexpression reverses the PANoptosis suppression caused by TRAF1 knockdown.","method":"Co-immunoprecipitation (OASL-ZBP1-PANoptosome interaction), TRAF1 knockdown/OASL overexpression rescue, functional assays (CCK-8, colony formation, TUNEL), in vivo H. pylori infection model","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP identifying OASL-ZBP1 interaction, functional rescue experiments, single lab, newly published","pmids":["41942799"],"is_preprint":false},{"year":2022,"finding":"OASL overexpression in SSc CD4+ T cells upregulates TET1 via IRF1 signaling, increasing hydroxymethylation of CD4+ T cell genomes and promoting aberrant expression of CD40L and CD70, driving CD4+ T cell hyperactivation; IRF1 binds the TET1 promoter as confirmed by dual luciferase reporter assay.","method":"RNA sequencing, overexpression experiments, dual luciferase reporter assay (IRF1 binding TET1 promoter), hydroxymethylation assays, flow cytometry","journal":"Arthritis research & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay for promoter binding, gain-of-function, single lab, limited mechanistic depth on direct OASL-IRF1 connection","pmids":["35183246"],"is_preprint":false}],"current_model":"Human OASL is an interferon-stimulated, catalytically inactive OAS family member that functions as a context-dependent innate immune regulator: during RNA virus infection, OASL enhances RIG-I signaling by mimicking K63-linked polyubiquitin through its C-terminal ubiquitin-like domains and by binding dsRNA through its OAS-like domain (which adopts an activated OAS1-like crystal structure); it also undergoes liquid-liquid phase condensation to scaffold RIPK3-ZBP1 necrosome assembly and drive virus-induced necroptosis; during DNA virus infection, OASL directly binds and non-competitively inhibits cGAS, suppressing cyclic GMP-AMP production and dampening IFN responses; mouse OASL1 additionally inhibits IRF7 translation to negatively regulate type I IFN production and traps viral RNAs in stress granules early in infection; OASL also regulates eNOS mRNA stability via a PI3K/Akt-miR-584 axis in endothelial cells, promotes autophagy-lysosomal degradation of MHC-I in cancer cells, and interacts with MBD1 through its ubiquitin-like domain."},"narrative":{"mechanistic_narrative":"OASL is an interferon-inducible, catalytically inactive member of the OAS family that has lost 2'-5' oligoadenylate synthetase activity and instead carries two C-terminal ubiquitin-like (UBL) domains that repurpose it as a context-dependent regulator of innate immune signaling [PMID:9722630]. Its induction is rapid and driven by IRF-3 independently of a functional type I IFN response, distinguishing it from IFN-dependent OAS1 [PMID:19203244]. During RNA virus infection, OASL acts as a positive co-activator of RIG-I: its UBL domains mimic K63-linked polyubiquitin to potentiate RIG-I signaling, while its OAS-like domain adopts an activated OAS1-like fold with a dsRNA-binding groove whose integrity is required for this co-activator function [PMID:24931123, PMID:25925578]. OASL also drives antiviral cell death by undergoing liquid-like phase condensation that scaffolds the RIPK3–ZBP1 necrosome, promoting RIPK3 fibril formation, autophosphorylation, and MLKL phosphorylation to execute virus-induced necroptosis [PMID:36604592]. In opposition to this antiviral arm, OASL directly and non-competitively binds cGAS independently of DNA and inhibits cyclic GMP-AMP synthesis, dampening STING-dependent type I IFN responses during DNA virus infection and in tumor microenvironments [PMID:30635239, PMID:41330170]. The mouse ortholog OASL1 functions predominantly as a negative regulator of type I IFN, repressing IRF7 translation and limiting IFN output, with loss of OASL1 sustaining IFN and accelerating viral clearance [PMID:23874199, PMID:27034232]. Beyond infection, OASL contributes to disease-relevant processes including endothelial NOS3 mRNA destabilization via a PI3K/Akt–miR-584 axis in atherosclerosis [PMID:36333342], and immune evasion in cancer through NBR1/autophagy-lysosomal degradation of MHC-I [PMID:39990208]. Rare OASL variants enhance type I IFN secretion by patient-derived dendritic cells, linking OASL function to systemic lupus erythematosus [PMID:37354689].","teleology":[{"year":1998,"claim":"Established OASL as a distinct OAS family member that has lost canonical synthetase activity but gained ubiquitin-like domains, setting up the central question of what function the UBL-bearing protein serves.","evidence":"cDNA cloning, genomic sequencing, and domain analysis of human p59OASL","pmids":["9722630"],"confidence":"Medium","gaps":["Lack of enzymatic activity inferred from sequence, not direct in vitro assay","No functional role assigned to the UBL domains"]},{"year":2004,"claim":"Identified the first OASL protein partner, showing the UBL domain mediates a specific interaction with the transcriptional repressor MBD1, indicating the UBL domains are protein-interaction modules.","evidence":"Yeast two-hybrid, in vitro pulldown, and reciprocal co-immunoprecipitation","pmids":["14728690"],"confidence":"Medium","gaps":["Functional consequence of OASL-MBD1 interaction not established","No link to antiviral or IFN biology"]},{"year":2009,"claim":"Placed OASL induction in an IRF-3-dependent, IFN-independent pathway, distinguishing its regulation from IFN-dependent OAS1 and positioning it as an early-response gene.","evidence":"Gene expression analysis during Sendai and influenza A virus infection with IRF-3 pathway dissection","pmids":["19203244"],"confidence":"Medium","gaps":["Does not define OASL molecular activity","Single lab"]},{"year":2012,"claim":"Functionally implicated the UBL domain in antiviral activity by showing splice variants retaining the UBL inhibit RNA viruses while those lacking it do not.","evidence":"RT-PCR cloning of natural splice variants, ectopic expression, and viral infection assays","pmids":["22531715"],"confidence":"Medium","gaps":["Molecular mechanism of UBL-mediated antiviral effect not yet defined","Virus-specificity (HSV-2 vs RNA viruses) unexplained"]},{"year":2013,"claim":"Revealed an opposing negative-regulatory role for the mouse ortholog OASL1, which suppresses sustained type I IFN, establishing that OASL family members can both enhance and dampen innate immunity.","evidence":"Oasl1 knockout mice in chronic LCMV infection with cytokine, flow cytometry, and viral titer readouts","pmids":["23874199"],"confidence":"High","gaps":["Molecular mechanism of IFN suppression not resolved in this study","Mouse-specific; human relevance unclear at this point"]},{"year":2014,"claim":"Defined the mechanism of OASL's RNA-virus antiviral activity: its UBL domain mimics K63-linked polyubiquitin to enhance RIG-I signaling, identifying RIG-I as the key effector.","evidence":"Reciprocal Co-IP, colocalization, RIG-I-dependent rescue, siRNA loss-of-function, and Oasl2 KO macrophages across multiple viruses","pmids":["24931123"],"confidence":"High","gaps":["Structural basis of polyubiquitin mimicry not yet shown","Role of the OAS-like domain undefined"]},{"year":2015,"claim":"Provided the structural and functional basis for the OAS-like domain, showing it adopts an activated OAS1-like fold and binds dsRNA, and that dsRNA binding is essential for RIG-I co-activation.","evidence":"X-ray crystallography, dsRNA binding assays, site-directed mutagenesis, and RIG-I reporter assays","pmids":["25925578"],"confidence":"High","gaps":["How dsRNA binding couples to UBL-mediated RIG-I enhancement not fully resolved"]},{"year":2018,"claim":"Resolved a temporal switch in OASL1 function: early stress-granule-mediated viral RNA trapping enhances RLR signaling, while late-stage interaction with IRF7 mRNA inhibits its translation to shut down IFN.","evidence":"Subcellular localization, stress granule assays, RNA-binding assays, and IRF7 translation assays","pmids":["29463066"],"confidence":"Medium","gaps":["Direct IRF7 mRNA binding mechanism not structurally defined","Mouse ortholog; human OASL behavior not addressed"]},{"year":2018,"claim":"Showed that a tree shrew ortholog bridges MDA5 and MAVS at mitochondria to potentiate IFN, extending the RNA-sensing co-activator role beyond RIG-I.","evidence":"Co-IP, subcellular fractionation, and gain/loss-of-function IFN reporter assays for tupaia OASL1","pmids":["33188074"],"confidence":"Medium","gaps":["Ortholog-specific; human OASL-MDA5/MAVS interaction not demonstrated","Single lab"]},{"year":2019,"claim":"Defined the DNA-virus arm of OASL biology: direct, non-competitive inhibition of cGAS that suppresses cGAMP and IFN, revealing OASL as a brake on the cGAS-STING pathway.","evidence":"Co-IP, in vitro cGAS enzymatic assays, OASL-deficient cells, Oasl2 KO mice, and cGAS epistasis across DNA viruses","pmids":["30635239"],"confidence":"High","gaps":["Structural basis of non-competitive cGAS inhibition not defined","How OASL switches between RIG-I enhancement and cGAS inhibition unclear"]},{"year":2022,"claim":"Extended OASL function into vascular biology, showing it stabilizes eNOS mRNA via a PI3K/Akt-miR-584 axis, with loss accelerating atherosclerosis.","evidence":"Endothelial-specific Oasl1 KO mice, atherosclerosis model, miRNA inhibitor rescue, and mRNA stability assays","pmids":["36333342"],"confidence":"High","gaps":["Direct molecular target of OASL in the PI3K/Akt-miR-584 axis not identified","Connection to its immune roles unclear"]},{"year":2022,"claim":"Placed OASL1 downstream of NRF2 in macrophages as a restraint on inflammatory and cell-death pathways during ischemia-reperfusion injury.","evidence":"Myeloid TXNIP KO mice, NRF2 disruption, and pathway analysis of TBK1/G3BP1 and apoptosis/necroptosis markers","pmids":["36035360"],"confidence":"Medium","gaps":["Direct OASL1 molecular targets in these pathways not defined","Single lab"]},{"year":2023,"claim":"Established a third antiviral mechanism: OASL undergoes liquid-like phase condensation to scaffold the RIPK3-ZBP1 necrosome and execute virus-induced necroptosis.","evidence":"Phase condensation assays, Co-IP, RIPK3 fibril/MLKL phosphorylation assays, and Oasl1 KO mouse infection model","pmids":["36604592"],"confidence":"High","gaps":["Which OASL domains drive condensation not fully mapped","Relationship between condensation and RIG-I co-activation unresolved"]},{"year":2023,"claim":"Connected the OASL1-IRF7 translational repression mechanism to antitumor immunity, showing loss boosts IFN-I and antitumor T/NK cell responses.","evidence":"Oasl1 KO mice in syngeneic tumor models with IRF7 protein, IFN-I, and immune cell readouts","pmids":["27034232"],"confidence":"Medium","gaps":["Mouse ortholog; human OASL translational control of IRF7 not shown","Single lab"]},{"year":2023,"claim":"Identified OASL as an upstream activator of mTORC1 driving tumor cell proliferation and invasion in stomach adenocarcinoma.","evidence":"siRNA knockdown, overexpression, mTOR/RPS6KB1 phosphorylation, rapamycin rescue, and xenograft assays","pmids":["36809539"],"confidence":"Medium","gaps":["Direct molecular link between OASL and mTORC1 activation unknown","Single lab"]},{"year":2023,"claim":"Linked OASL function to a human Mendelian/autoimmune phenotype, showing rare SLE-associated variants causally enhance type I IFN secretion.","evidence":"Patient-derived iPSC-differentiated DCs with bidirectional CRISPR genome editing and IFN secretion assays","pmids":["37354689"],"confidence":"Medium","gaps":["Mechanism by which variants alter OASL function not defined","Single lab"]},{"year":2024,"claim":"Demonstrated a direct antiviral effector role distinct from signaling, targeting IBDV VP2 for p62/SQSTM1-mediated autophagic degradation.","evidence":"Co-IP, autophagy pathway assays, and VP2 K316R mutagenesis with viral replication readouts","pmids":["38639485"],"confidence":"Medium","gaps":["Whether this autophagy-targeting role generalizes to other viral proteins unknown","Single lab"]},{"year":2024,"claim":"Identified Pi16 as an OASL partner that promotes pancreatic cancer proliferation through OASL.","evidence":"Co-IP, Pi16 CRISPR knockout, and OASL functional rescue in proliferation assays","pmids":["38353288"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation; limited mechanistic detail on how OASL mediates proliferation","Direct binding interface undefined"]},{"year":2025,"claim":"Defined an immune-evasion mechanism in pancreatic cancer whereby OASL drives NBR1-mediated autophagy-lysosomal degradation of MHC-I to limit CD8+ T-cell infiltration.","evidence":"Co-IP, flow cytometry, immunofluorescence, and orthotopic PDAC mouse model with OASL knockdown","pmids":["39990208"],"confidence":"Medium","gaps":["Direct OASL-NBR1 binding interface not defined","Single lab"]},{"year":2025,"claim":"Placed OASL in a JAK1-STAT1 axis driving MAPK-dependent keratinocyte hyperproliferation in psoriasis.","evidence":"OASL knockdown/overexpression in HaCaT cells, JAK1 inhibitor treatment, and imiquimod psoriasis model","pmids":["40360089"],"confidence":"Low","gaps":["Limited mechanistic detail; direct OASL-p38 link not established","Single lab"]},{"year":2025,"claim":"Confirmed and extended the cGAS-inhibitory role to the tumor microenvironment, showing OASL suppresses cGAS-STING antitumor immunity and sustains matrix stiffness in HCC.","evidence":"Co-IP, immunofluorescence, cGAMP ELISA, STING inhibitor rescue, and subcutaneous HCC mouse model","pmids":["41330170"],"confidence":"Medium","gaps":["Mechanistic basis of matrix stiffness regulation not defined","Single lab"]},{"year":2025,"claim":"Showed that intrinsic, pre-infection OASL expression is required for robust type III IFN induction during influenza, identifying OASL as a determinant of cellular IFN heterogeneity.","evidence":"Temporal single-cell RNA-seq and OASL loss-of-function validation in IAV infection","pmids":["41468430"],"confidence":"Medium","gaps":["Molecular mechanism linking OASL to IFNL induction not defined","Single lab"]},{"year":2026,"claim":"Linked OASL to PANoptosis, showing TRAF1 transcriptionally activates OASL, which associates with the ZBP1-PANoptosome during H. pylori infection.","evidence":"Co-IP of OASL-ZBP1-PANoptosome, TRAF1 knockdown/OASL overexpression rescue, and in vivo H. pylori model","pmids":["41942799"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation; 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sets","date":"2024-07-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.24309917","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.658906","title":"Omega-3 Fatty Acid Synergy with Glucocorticoid in Lupus Macrophages: Targeting Pathogenic Pathways to Reduce Steroid Dependence","date":"2025-06-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.658906","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33428,"output_tokens":6472,"usd":0.098682,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15199,"output_tokens":6477,"usd":0.11896,"stage2_stop_reason":"end_turn"},"total_usd":0.217642,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"OASL (p59OASL) was identified as a novel OAS family member with a conserved N-terminal OAS-like domain but lacking 2'-5' oligoadenylate synthetase activity; its C-terminus contains two ubiquitin-like domains, distinguishing it from other OAS family members.\",\n      \"method\": \"cDNA cloning, genomic sequencing, sequence/domain analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — full-length cDNA characterization and domain analysis in single study; lack of enzymatic activity established by sequence inference, not yet by direct in vitro assay\",\n      \"pmids\": [\"9722630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OASL (p59OASL) interacts with the transcriptional repressor MBD1 (methyl CpG-binding protein 1) via its C-terminal ubiquitin-like domain; the interaction was confirmed by yeast two-hybrid, in vitro pulldown, and in vivo co-immunoprecipitation, and was specific (OASL did not interact with other MBD family members, and MBD1 did not interact with OAS1).\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vitro pulldown and yeast two-hybrid, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14728690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OASL gene induction by viral infection is rapid and mediated by IRF-3 (IFN regulatory factor 3), independently of a functional type I IFN response, in contrast to OAS1 which requires type I IFN signaling for its induction.\",\n      \"method\": \"Gene expression analysis during Sendai virus and Influenza A virus infection; IRF-3 pathway dissection\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by functional dissection (IRF-3-dependent vs IFN-dependent induction), single lab\",\n      \"pmids\": [\"19203244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A splice variant of human OASL (OASL d), derived by deletion of exons 4 and 5 and retaining the ubiquitin-like domain, exhibits antiviral activity against RNA viruses (EV71, VSV) but not HSV-2; OASL b, which lacks the ubiquitin-like domain but shares the N-terminus, has no antiviral activity, implicating the ubiquitin-like domain in antiviral function.\",\n      \"method\": \"RT-PCR cloning, ectopic expression, viral infection assays, immunoblotting\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain dissection using natural splice variants with gain-of-function experiments, single lab\",\n      \"pmids\": [\"22531715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse OASL1 negatively regulates type I IFN production; OASL1 deficiency leads to sustained type I IFN levels (primarily from plasmacytoid dendritic cells) during chronic LCMV infection, accelerated viral clearance, and restored CD8+ T-cell function, demonstrating OASL1 as a negative regulator of the innate antiviral response.\",\n      \"method\": \"Oasl1 knockout mice, LCMV chronic infection model, serum cytokine measurements, flow cytometry, viral titer assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse model with multiple defined cellular and molecular phenotypes, independently replicated in subsequent studies\",\n      \"pmids\": [\"23874199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human OASL enhances RIG-I activation by mimicking K63-linked polyubiquitin through its C-terminal ubiquitin-like domain; OASL interacts and colocalizes with RIG-I, and its expression suppresses replication of multiple RNA viruses in a RIG-I-dependent manner; loss of OASL reduces RIG-I signaling and enhances virus replication. Mouse Oasl2 is the functionally equivalent ortholog.\",\n      \"method\": \"Co-immunoprecipitation, colocalization imaging, RIG-I-dependent rescue experiments, loss-of-function (siRNA knockdown), gain-of-function (overexpression), Oasl2 KO bone-marrow-derived macrophages, multi-virus replication assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, colocalization, domain-specific mechanism (UBL mimicking polyubiquitin), RIG-I epistasis, KO mouse cells, multiple orthogonal methods, replicated in subsequent studies\",\n      \"pmids\": [\"24931123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The OAS-like domain of human OASL adopts a crystal structure resembling activated OAS1 and contains a positively charged dsRNA binding groove; OASL binds dsRNA through this domain, and mutation of key residues in the dsRNA binding site abolishes the ability of OASL to enhance RIG-I signaling, demonstrating that dsRNA binding is essential for OASL's co-activator function.\",\n      \"method\": \"X-ray crystallography, dsRNA binding assays, site-directed mutagenesis, RIG-I signaling reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assay; multiple orthogonal methods in one study establishing mechanism\",\n      \"pmids\": [\"25925578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mouse OASL1 forms stress granules that trap viral RNAs during early viral infection, promoting efficient RLR (RIG-I-like receptor) signaling; this stress granule formation depends on the RNA binding activity of OASL1. In late stages of infection, OASL1 interacts with IRF7 mRNA transcripts to inhibit IRF7 translation, thereby downregulating type I IFN production.\",\n      \"method\": \"Subcellular localization imaging, stress granule assays, viral RNA trapping experiments, RNA-binding assays, IRF7 translation assays\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (stress granule formation linked to RLR signaling enhancement), and IRF7 mRNA interaction, single lab\",\n      \"pmids\": [\"29463066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human OASL and mouse Oasl2 directly bind cGAS (independently of dsDNA) and inhibit cGAS enzymatic activity (cyclic GMP-AMP production) via non-competitive inhibition, thereby suppressing type I IFN induction during DNA virus infection; OASL-deficient cells and Oasl2-/- mice show increased IFN production and reduced DNA virus (vaccinia, HSV, adenovirus) replication, and cGAS is required for this phenotype.\",\n      \"method\": \"Co-immunoprecipitation, cGAS enzymatic activity assays, OASL-deficient human cells and Oasl2 KO mice, multi-virus replication assays, genetic epistasis (cGAS knockdown rescue)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding demonstrated by Co-IP, enzymatic inhibition assayed in vitro, genetic epistasis with cGAS, KO mouse model, multiple viruses; replicated by subsequent studies\",\n      \"pmids\": [\"30635239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tupaia OASL1 (tree shrew ortholog) associates with mitochondria and directly interacts with both MDA5 and MAVS via its OAS and UBL domains; upon RNA virus infection, tOASL1 enhances MDA5-MAVS interaction to potentiate type I IFN signaling.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, overexpression and knockdown assays, IFN signaling reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing direct interaction with MDA5 and MAVS, localization data, gain/loss-of-function, single lab\",\n      \"pmids\": [\"33188074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OASL1/OASL regulates eNOS (NOS3) mRNA stability in endothelial cells; endothelial Oasl1 deficiency leads to reduced eNOS expression through PI3K/Akt-dependent upregulation of miR-584 (a negative regulator of NOS3 mRNA), resulting in impaired NO bioavailability and accelerated atherosclerotic plaque progression. miR-584 inhibition rescues the effects of OASL knockdown.\",\n      \"method\": \"Endothelial-specific Oasl1 knockout mice, atherosclerosis model, miRNA inhibitor rescue experiments, PI3K/Akt pathway inhibition, mRNA stability assays, Western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO mouse model, mechanistic pathway dissection (PI3K/Akt → OASL → miR-584 → NOS3 mRNA), rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"36333342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mouse OASL1 acts downstream of NRF2 in macrophages; OASL1 deficiency enhances G3BP1- and TBK1-mediated inflammatory responses and induces apoptosis/necroptosis via APAF1/cytochrome c/caspase-9 and RIPK3 pathways during hepatic ischemia-reperfusion injury.\",\n      \"method\": \"Myeloid-specific TXNIP KO mice, NRF2 disruption experiments, OASL1 deficiency experiments, pathway analysis (STING/TBK1, apoptosis/necroptosis markers), histological and biochemical assays\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model placing OASL1 downstream of NRF2 and upstream of TBK1/G3BP1 and apoptotic machinery, single lab, multiple pathway readouts\",\n      \"pmids\": [\"36035360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OASL promotes virus-induced necroptosis by undergoing liquid-like phase condensation, which scaffolds the RIPK3-ZBP1 necrosome complex; OASL phase-separated droplets recruit RIPK3 and ZBP1 via protein-protein interactions, providing spatial segregation that facilitates RIPK3 amyloid-like fibril formation, autophosphorylation, and subsequent MLKL phosphorylation. Oasl1-deficient mice show severely impaired necroptosis and succumb to uncontrolled viral infection.\",\n      \"method\": \"Phase condensation assays, co-immunoprecipitation, RIPK3 fibril/amyloid assays, MLKL phosphorylation assays, Oasl1 KO mouse viral infection model, live cell imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (phase condensation, Co-IP, fibril assays, phosphorylation, KO mouse), mechanistic pathway established with in vitro and in vivo validation\",\n      \"pmids\": [\"36604592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OASL1 negatively regulates IRF7 translation (not transcription), thereby reducing type I IFN production; mouse Oasl1 KO leads to increased IRF7 protein and enhanced type I IFN in response to tumors, promoting antitumor immunity with increased CD8+ T cells, NK cells, and CD8α+ DCs in tumors.\",\n      \"method\": \"Oasl1 KO mice, syngeneic tumor transplant models, IRF7 protein measurement, flow cytometry, IFN-I measurement\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined molecular mechanism (IRF7 protein level increase), multiple cellular phenotypes, single lab\",\n      \"pmids\": [\"27034232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OASL knockdown in stomach adenocarcinoma cells suppresses mTORC1 signaling (reduced p-mTOR and p-RPS6KB1), inhibiting cell proliferation, migration, and invasion; OASL overexpression activates mTORC1 signaling, and rapamycin reverses OASL overexpression-induced tumor cell growth, establishing OASL as an upstream activator of mTORC1 in STAD.\",\n      \"method\": \"siRNA knockdown, overexpression, mTOR/RPS6KB1 phosphorylation Western blot, rapamycin rescue, xenograft tumor formation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue placing OASL upstream of mTORC1, single lab\",\n      \"pmids\": [\"36809539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rare OASL variants (R60W, T261S, A447V, 202Q) found in SLE patients enhance type I IFN secretion by dendritic cells differentiated from patient-derived iPSCs; genome editing of the 202Q variant to wild-type 202R reduced IFN secretion, and introduction of 202Q into wild-type iPSCs enhanced it, confirming functional causality.\",\n      \"method\": \"Patient-derived iPSC differentiation to DCs, CRISPR/Cas9 genome editing, IFN secretion assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic genome editing with bidirectional functional consequence, patient-derived cells, single lab\",\n      \"pmids\": [\"37354689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OASL interacts with viral protein VP2 of IBDV (infectious bursal disease virus) and targets it for degradation via the autophagy receptor p62/SQSTM1 through the autophagy pathway; lysine 316 of VP2 is the critical site for this autophagy-mediated degradation, and K316R mutation abolishes VP2 degradation and enhances IBDV replication.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown assays, autophagy pathway assays, site-directed mutagenesis (VP2 K316R), viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis identifying critical residue, autophagy pathway validation, single lab\",\n      \"pmids\": [\"38639485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pi16 (peptidase inhibitor 16) binds to OASL by co-immunoprecipitation and promotes pancreatic ductal adenocarcinoma cell proliferation via OASL; functional rescue experiments confirmed that Pi16's proliferative effect depends on OASL.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR/Cas9 knockout of Pi16, functional rescue with OASL, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction, functional rescue, single lab, limited mechanistic detail on how OASL mediates proliferation\",\n      \"pmids\": [\"38353288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OASL promotes immune evasion in pancreatic ductal adenocarcinoma by enhancing NBR1-mediated autophagy-lysosomal degradation of MHC-I; OASL knockdown restores total and surface MHC-I levels, increases CD8+ T-cell infiltration, and slows tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry, Western blot, immunofluorescence, orthotopic PDAC mouse model, OASL knockdown\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying OASL-NBR1-MHC-I pathway, in vivo and in vitro validation, multiple methods, single lab\",\n      \"pmids\": [\"39990208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OASL promotes mTOR-independent and MAPK (p38)-dependent keratinocyte hyperproliferation and inflammatory/lipid metabolic dysregulation in psoriasis; OASL expression is regulated by the JAK1-STAT1 axis (Upadacitinib inhibits STAT1 and reduces OASL), and OASL knockdown suppresses p38 MAPK activation.\",\n      \"method\": \"OASL knockdown and overexpression in HaCaT cells, JAK1 inhibitor treatment, p38 MAPK pathway analysis, imiquimod-induced psoriasis mouse model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain/loss-of-function placing OASL in JAK1-STAT1 axis upstream of p38 MAPK, single lab, limited mechanistic detail\",\n      \"pmids\": [\"40360089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OASL directly binds cGAS (confirmed by Co-IP and immunofluorescence) and inhibits cGAMP generation, reducing STING-mediated antitumor immunity and sustaining matrix stiffness in hepatocellular carcinoma; OASL knockdown activates cGAS-STING signaling and promotes M1 macrophage polarization, and STING inhibitor C-176 reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ELISA (cGAMP), Western blot, flow cytometry, subcutaneous HCC mouse model, STING inhibitor rescue\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct OASL-cGAS binding confirmed by Co-IP and immunofluorescence, enzymatic inhibition (cGAMP), genetic epistasis with STING inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"41330170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Intrinsic (pre-infection) expression of OASL is essential for robust type III IFN (IFNL) induction during influenza A virus infection; single-cell RNA-seq analysis of temporal infection data identified OASL as a correlate of IFN induction potential, and validation experiments confirmed OASL as necessary for this heterogeneous cellular IFN response.\",\n      \"method\": \"Temporal single-cell RNA sequencing, OASL knockdown/loss-of-function validation, IAV infection model, IFNL induction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq discovery validated by loss-of-function experiments establishing OASL as necessary for IFNL induction, single lab\",\n      \"pmids\": [\"41468430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OASL interacts with the ZBP1-PANoptosome complex via co-immunoprecipitation; TRAF1 transcriptionally activates OASL, and OASL promotes PANoptosis (combined apoptosis/necroptosis/pyroptosis) during H. pylori infection of gastric epithelial cells; OASL overexpression reverses the PANoptosis suppression caused by TRAF1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation (OASL-ZBP1-PANoptosome interaction), TRAF1 knockdown/OASL overexpression rescue, functional assays (CCK-8, colony formation, TUNEL), in vivo H. pylori infection model\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP identifying OASL-ZBP1 interaction, functional rescue experiments, single lab, newly published\",\n      \"pmids\": [\"41942799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OASL overexpression in SSc CD4+ T cells upregulates TET1 via IRF1 signaling, increasing hydroxymethylation of CD4+ T cell genomes and promoting aberrant expression of CD40L and CD70, driving CD4+ T cell hyperactivation; IRF1 binds the TET1 promoter as confirmed by dual luciferase reporter assay.\",\n      \"method\": \"RNA sequencing, overexpression experiments, dual luciferase reporter assay (IRF1 binding TET1 promoter), hydroxymethylation assays, flow cytometry\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay for promoter binding, gain-of-function, single lab, limited mechanistic depth on direct OASL-IRF1 connection\",\n      \"pmids\": [\"35183246\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human OASL is an interferon-stimulated, catalytically inactive OAS family member that functions as a context-dependent innate immune regulator: during RNA virus infection, OASL enhances RIG-I signaling by mimicking K63-linked polyubiquitin through its C-terminal ubiquitin-like domains and by binding dsRNA through its OAS-like domain (which adopts an activated OAS1-like crystal structure); it also undergoes liquid-liquid phase condensation to scaffold RIPK3-ZBP1 necrosome assembly and drive virus-induced necroptosis; during DNA virus infection, OASL directly binds and non-competitively inhibits cGAS, suppressing cyclic GMP-AMP production and dampening IFN responses; mouse OASL1 additionally inhibits IRF7 translation to negatively regulate type I IFN production and traps viral RNAs in stress granules early in infection; OASL also regulates eNOS mRNA stability via a PI3K/Akt-miR-584 axis in endothelial cells, promotes autophagy-lysosomal degradation of MHC-I in cancer cells, and interacts with MBD1 through its ubiquitin-like domain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OASL is an interferon-inducible, catalytically inactive member of the OAS family that has lost 2'-5' oligoadenylate synthetase activity and instead carries two C-terminal ubiquitin-like (UBL) domains that repurpose it as a context-dependent regulator of innate immune signaling [#0]. Its induction is rapid and driven by IRF-3 independently of a functional type I IFN response, distinguishing it from IFN-dependent OAS1 [#2]. During RNA virus infection, OASL acts as a positive co-activator of RIG-I: its UBL domains mimic K63-linked polyubiquitin to potentiate RIG-I signaling, while its OAS-like domain adopts an activated OAS1-like fold with a dsRNA-binding groove whose integrity is required for this co-activator function [#5, #6]. OASL also drives antiviral cell death by undergoing liquid-like phase condensation that scaffolds the RIPK3–ZBP1 necrosome, promoting RIPK3 fibril formation, autophosphorylation, and MLKL phosphorylation to execute virus-induced necroptosis [#12]. In opposition to this antiviral arm, OASL directly and non-competitively binds cGAS independently of DNA and inhibits cyclic GMP-AMP synthesis, dampening STING-dependent type I IFN responses during DNA virus infection and in tumor microenvironments [#8, #20]. The mouse ortholog OASL1 functions predominantly as a negative regulator of type I IFN, repressing IRF7 translation and limiting IFN output, with loss of OASL1 sustaining IFN and accelerating viral clearance [#4, #13]. Beyond infection, OASL contributes to disease-relevant processes including endothelial NOS3 mRNA destabilization via a PI3K/Akt–miR-584 axis in atherosclerosis [#10], and immune evasion in cancer through NBR1/autophagy-lysosomal degradation of MHC-I [#18]. Rare OASL variants enhance type I IFN secretion by patient-derived dendritic cells, linking OASL function to systemic lupus erythematosus [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established OASL as a distinct OAS family member that has lost canonical synthetase activity but gained ubiquitin-like domains, setting up the central question of what function the UBL-bearing protein serves.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, and domain analysis of human p59OASL\",\n      \"pmids\": [\"9722630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lack of enzymatic activity inferred from sequence, not direct in vitro assay\", \"No functional role assigned to the UBL domains\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the first OASL protein partner, showing the UBL domain mediates a specific interaction with the transcriptional repressor MBD1, indicating the UBL domains are protein-interaction modules.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, and reciprocal co-immunoprecipitation\",\n      \"pmids\": [\"14728690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of OASL-MBD1 interaction not established\", \"No link to antiviral or IFN biology\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed OASL induction in an IRF-3-dependent, IFN-independent pathway, distinguishing its regulation from IFN-dependent OAS1 and positioning it as an early-response gene.\",\n      \"evidence\": \"Gene expression analysis during Sendai and influenza A virus infection with IRF-3 pathway dissection\",\n      \"pmids\": [\"19203244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define OASL molecular activity\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Functionally implicated the UBL domain in antiviral activity by showing splice variants retaining the UBL inhibit RNA viruses while those lacking it do not.\",\n      \"evidence\": \"RT-PCR cloning of natural splice variants, ectopic expression, and viral infection assays\",\n      \"pmids\": [\"22531715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of UBL-mediated antiviral effect not yet defined\", \"Virus-specificity (HSV-2 vs RNA viruses) unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed an opposing negative-regulatory role for the mouse ortholog OASL1, which suppresses sustained type I IFN, establishing that OASL family members can both enhance and dampen innate immunity.\",\n      \"evidence\": \"Oasl1 knockout mice in chronic LCMV infection with cytokine, flow cytometry, and viral titer readouts\",\n      \"pmids\": [\"23874199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of IFN suppression not resolved in this study\", \"Mouse-specific; human relevance unclear at this point\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the mechanism of OASL's RNA-virus antiviral activity: its UBL domain mimics K63-linked polyubiquitin to enhance RIG-I signaling, identifying RIG-I as the key effector.\",\n      \"evidence\": \"Reciprocal Co-IP, colocalization, RIG-I-dependent rescue, siRNA loss-of-function, and Oasl2 KO macrophages across multiple viruses\",\n      \"pmids\": [\"24931123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of polyubiquitin mimicry not yet shown\", \"Role of the OAS-like domain undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural and functional basis for the OAS-like domain, showing it adopts an activated OAS1-like fold and binds dsRNA, and that dsRNA binding is essential for RIG-I co-activation.\",\n      \"evidence\": \"X-ray crystallography, dsRNA binding assays, site-directed mutagenesis, and RIG-I reporter assays\",\n      \"pmids\": [\"25925578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dsRNA binding couples to UBL-mediated RIG-I enhancement not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved a temporal switch in OASL1 function: early stress-granule-mediated viral RNA trapping enhances RLR signaling, while late-stage interaction with IRF7 mRNA inhibits its translation to shut down IFN.\",\n      \"evidence\": \"Subcellular localization, stress granule assays, RNA-binding assays, and IRF7 translation assays\",\n      \"pmids\": [\"29463066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IRF7 mRNA binding mechanism not structurally defined\", \"Mouse ortholog; human OASL behavior not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that a tree shrew ortholog bridges MDA5 and MAVS at mitochondria to potentiate IFN, extending the RNA-sensing co-activator role beyond RIG-I.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, and gain/loss-of-function IFN reporter assays for tupaia OASL1\",\n      \"pmids\": [\"33188074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-specific; human OASL-MDA5/MAVS interaction not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the DNA-virus arm of OASL biology: direct, non-competitive inhibition of cGAS that suppresses cGAMP and IFN, revealing OASL as a brake on the cGAS-STING pathway.\",\n      \"evidence\": \"Co-IP, in vitro cGAS enzymatic assays, OASL-deficient cells, Oasl2 KO mice, and cGAS epistasis across DNA viruses\",\n      \"pmids\": [\"30635239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of non-competitive cGAS inhibition not defined\", \"How OASL switches between RIG-I enhancement and cGAS inhibition unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended OASL function into vascular biology, showing it stabilizes eNOS mRNA via a PI3K/Akt-miR-584 axis, with loss accelerating atherosclerosis.\",\n      \"evidence\": \"Endothelial-specific Oasl1 KO mice, atherosclerosis model, miRNA inhibitor rescue, and mRNA stability assays\",\n      \"pmids\": [\"36333342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of OASL in the PI3K/Akt-miR-584 axis not identified\", \"Connection to its immune roles unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed OASL1 downstream of NRF2 in macrophages as a restraint on inflammatory and cell-death pathways during ischemia-reperfusion injury.\",\n      \"evidence\": \"Myeloid TXNIP KO mice, NRF2 disruption, and pathway analysis of TBK1/G3BP1 and apoptosis/necroptosis markers\",\n      \"pmids\": [\"36035360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OASL1 molecular targets in these pathways not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a third antiviral mechanism: OASL undergoes liquid-like phase condensation to scaffold the RIPK3-ZBP1 necrosome and execute virus-induced necroptosis.\",\n      \"evidence\": \"Phase condensation assays, Co-IP, RIPK3 fibril/MLKL phosphorylation assays, and Oasl1 KO mouse infection model\",\n      \"pmids\": [\"36604592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which OASL domains drive condensation not fully mapped\", \"Relationship between condensation and RIG-I co-activation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected the OASL1-IRF7 translational repression mechanism to antitumor immunity, showing loss boosts IFN-I and antitumor T/NK cell responses.\",\n      \"evidence\": \"Oasl1 KO mice in syngeneic tumor models with IRF7 protein, IFN-I, and immune cell readouts\",\n      \"pmids\": [\"27034232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mouse ortholog; human OASL translational control of IRF7 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified OASL as an upstream activator of mTORC1 driving tumor cell proliferation and invasion in stomach adenocarcinoma.\",\n      \"evidence\": \"siRNA knockdown, overexpression, mTOR/RPS6KB1 phosphorylation, rapamycin rescue, and xenograft assays\",\n      \"pmids\": [\"36809539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between OASL and mTORC1 activation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked OASL function to a human Mendelian/autoimmune phenotype, showing rare SLE-associated variants causally enhance type I IFN secretion.\",\n      \"evidence\": \"Patient-derived iPSC-differentiated DCs with bidirectional CRISPR genome editing and IFN secretion assays\",\n      \"pmids\": [\"37354689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which variants alter OASL function not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a direct antiviral effector role distinct from signaling, targeting IBDV VP2 for p62/SQSTM1-mediated autophagic degradation.\",\n      \"evidence\": \"Co-IP, autophagy pathway assays, and VP2 K316R mutagenesis with viral replication readouts\",\n      \"pmids\": [\"38639485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this autophagy-targeting role generalizes to other viral proteins unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Pi16 as an OASL partner that promotes pancreatic cancer proliferation through OASL.\",\n      \"evidence\": \"Co-IP, Pi16 CRISPR knockout, and OASL functional rescue in proliferation assays\",\n      \"pmids\": [\"38353288\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation; limited mechanistic detail on how OASL mediates proliferation\", \"Direct binding interface undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an immune-evasion mechanism in pancreatic cancer whereby OASL drives NBR1-mediated autophagy-lysosomal degradation of MHC-I to limit CD8+ T-cell infiltration.\",\n      \"evidence\": \"Co-IP, flow cytometry, immunofluorescence, and orthotopic PDAC mouse model with OASL knockdown\",\n      \"pmids\": [\"39990208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OASL-NBR1 binding interface not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed OASL in a JAK1-STAT1 axis driving MAPK-dependent keratinocyte hyperproliferation in psoriasis.\",\n      \"evidence\": \"OASL knockdown/overexpression in HaCaT cells, JAK1 inhibitor treatment, and imiquimod psoriasis model\",\n      \"pmids\": [\"40360089\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic detail; direct OASL-p38 link not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed and extended the cGAS-inhibitory role to the tumor microenvironment, showing OASL suppresses cGAS-STING antitumor immunity and sustains matrix stiffness in HCC.\",\n      \"evidence\": \"Co-IP, immunofluorescence, cGAMP ELISA, STING inhibitor rescue, and subcutaneous HCC mouse model\",\n      \"pmids\": [\"41330170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of matrix stiffness regulation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that intrinsic, pre-infection OASL expression is required for robust type III IFN induction during influenza, identifying OASL as a determinant of cellular IFN heterogeneity.\",\n      \"evidence\": \"Temporal single-cell RNA-seq and OASL loss-of-function validation in IAV infection\",\n      \"pmids\": [\"41468430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking OASL to IFNL induction not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked OASL to PANoptosis, showing TRAF1 transcriptionally activates OASL, which associates with the ZBP1-PANoptosome during H. pylori infection.\",\n      \"evidence\": \"Co-IP of OASL-ZBP1-PANoptosome, TRAF1 knockdown/OASL overexpression rescue, and in vivo H. pylori model\",\n      \"pmids\": [\"41942799\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation; newly published and unreplicated\", \"Direct OASL contribution to PANoptosome assembly undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OASL switches between its opposing roles — enhancing RIG-I/RLR signaling versus inhibiting cGAS, and promoting versus suppressing IFN — remains unresolved at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining context-dependent partner selection (RIG-I vs cGAS)\", \"Determinants of human vs mouse functional divergence (enhancer vs IFN repressor) unclear\", \"How phase condensation, dsRNA binding, and UBL polyubiquitin mimicry are coordinated within one protein not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 8, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [16, 18]}\n    ],\n    \"complexes\": [\n      \"RIPK3-ZBP1 necrosome\",\n      \"ZBP1-PANoptosome\"\n    ],\n    \"partners\": [\n      \"RIGI\",\n      \"CGAS\",\n      \"RIPK3\",\n      \"ZBP1\",\n      \"MBD1\",\n      \"NBR1\",\n      \"MDA5\",\n      \"MAVS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}