{"gene":"RNASEL","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1999,"finding":"Full activation of RNase L requires binding of 2-5A oligonucleotides within ankyrin repeats 6 to 9 (amino acid positions 212-339). The protein kinase and ribonuclease domains (amino acids 340-741) are sufficient for constitutively active, 2-5A-unresponsive enzyme, demonstrating that ankyrin repeats act as key modulators of RNase L activity.","method":"Expression of truncated RNase L forms via vaccinia virus recombinants in cultured cells, with and without co-expression of 2-5A synthetase; functional activity comparison","journal":"Journal of interferon & cytokine research","confidence":"High","confidence_rationale":"Tier 1 — in vivo reconstitution with domain truncation mutants, rigorous functional comparison","pmids":["10090396"],"is_preprint":false},{"year":2002,"finding":"The RNASEL variant Arg462Gln has approximately three times less enzymatic (RNase) activity than the wild-type protein.","method":"Enzymatic activity assay comparing wild-type and R462Q variant proteins","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic activity assay; widely replicated across multiple independent studies","pmids":["12415269"],"is_preprint":false},{"year":2004,"finding":"RNase L mediates apoptosis of prostate cancer cells in response to 2-5A, topoisomerase I inhibitor/TRAIL combination, and this apoptotic signaling involves c-Jun N-terminal kinase (JNK). RNase L-deficient DU145 cells were highly resistant to apoptosis from these stimuli, while knockdown of the RNase L inhibitor RLI (HP68) enhanced apoptosis.","method":"Stable siRNA knockdown of RNase L in DU145 prostate cancer cells; apoptosis assays with 2-5A, camptothecin/TRAIL combinations; JNK inhibitor experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — clean KD with specific phenotypic readout, multiple orthogonal treatments, inhibitor validation of pathway","pmids":["15604285"],"is_preprint":false},{"year":2004,"finding":"RNase L regulates the stability of mitochondrial DNA-encoded mRNAs (mt-mRNAs). In RNase-L-null mouse embryo fibroblasts, monensin-induced decrease in mt-mRNA half-life was reduced (>6h vs. 3h in wild-type), and induction of RNase-L further decreased mt-mRNA half-life to 1.5h. Nuclear-encoded beta-actin mRNA stability was unaffected.","method":"RNase-L(-/-) vs. wild-type mouse embryo fibroblasts; actinomycin D transcription termination assay; RNase-L overexpression in 3T3 fibroblasts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — KO with specific phenotypic readout and OE confirmation, single study","pmids":["15522195"],"is_preprint":false},{"year":2005,"finding":"BRCA1 and STAT1 are required for IFN-gamma-induced transcriptional activation of 2,5-OAS, the upstream activator of RNase L, positioning BRCA1 as an upstream regulator of the OAS/RNase L apoptotic pathway. IFN-gamma-induced apoptosis was dependent on 2,5-OAS induction.","method":"Transient transfection of 2,5-OAS into breast cancer cell lines (colony growth/apoptosis assays); siRNA/dominant-negative BRCA1 and STAT1 knockdown; functional apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by KD with functional readout, single lab","pmids":["15940267"],"is_preprint":false},{"year":2006,"finding":"RNase L induces cellular senescence: ectopic expression of RNase L induced senescent morphology, decreased DNA synthesis, increased SA-β-galactosidase activity, and accelerated replicative senescence. RNase-L-null fibroblasts showed retarded senescence. Activation of endogenous RNase L by 2-5A induced senescence in parental WI38 fibroblasts but apoptosis in SV40-transformed cells. RNase-L(-/-) mice survived 31.7% longer than wild-type mice.","method":"Ectopic RNase L expression; RNase-L(-/-) vs. wild-type fibroblasts; 2-5A transfection; SA-β-gal assays; BrdU incorporation; mouse lifespan studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (OE, KO cells, KO mice, 2-5A activation), replicated across cell types","pmids":["17130839"],"is_preprint":false},{"year":2007,"finding":"The 3'-UTR of RNASEL mRNA mediates post-transcriptional regulation of RNase L expression by decreasing mRNA stability. Eight AU-rich elements (AREs) were identified; AREs 7 and 8 serve a positive regulatory function. The RNA-binding protein HuR stabilizes RNase-L mRNA by binding within the region of AREs 7 and 8, enhancing RNase-L expression and antiviral activity.","method":"5'-RACE; chimeric beta-globin-3'-UTR reporter constructs; deletion analysis; HuR co-transfection; mRNA stability assays; immunoprecipitation of HuR-RNase-L mRNA complex; antiviral activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including reporter assays, mutagenesis/deletion, co-IP, and functional antiviral readout","pmids":["17237228"],"is_preprint":false},{"year":2008,"finding":"RNase L is required for the antibacterial immune response. RNase-L(-/-) mice showed dramatically increased mortality after Bacillus anthracis and E. coli challenge due to increased bacterial load and compromised immune response. RNase-L is required for optimal induction of proinflammatory cytokines (TNF-alpha, IL-6, IL-12) and regulates cathepsin-E expression and endosome-associated activities that eliminate internalized bacteria.","method":"RNase-L(-/-) mouse infection models (B. anthracis, E. coli); bacterial load quantification; cytokine measurements; cathepsin-E expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined phenotype, multiple pathogens, multiple mechanistic readouts","pmids":["19075243"],"is_preprint":false},{"year":2009,"finding":"NOD2 interacts with 2'-5'-oligoadenylate synthetase type 2 (OAS2), an upstream activator of RNase L. This interaction was confirmed by immunoprecipitation of endogenous OAS2 with NOD2 in THP-1 cells, and overexpression of NOD2 enhanced RNase-L activity in poly(I:C)-treated cells.","method":"Proteomics/pulldown; co-immunoprecipitation in HEK and THP-1 cells; RNase-L activity assay after NOD2 overexpression and poly(I:C) treatment","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 3 — reciprocal co-IP confirmed, functional RNase-L activity readout; single lab","pmids":["19853919"],"is_preprint":false},{"year":2012,"finding":"The miR-29 family represses RNase-L protein expression via four target sites within the RNASEL 3'-UTR. In K562 CML cells, RNase-L knockdown inhibits proliferation in vitro and tumor growth in a xenograft model, revealing an oncogenic role for RNase-L in CML.","method":"Luciferase reporter with RNASEL 3'-UTR; site mutagenesis; stable RNase-L knockdown in K562 cells; in vitro proliferation assay; xenograft tumor model","journal":"Journal of interferon & cytokine research","confidence":"High","confidence_rationale":"Tier 1-2 — reporter + mutagenesis + functional KD in vitro and in vivo xenograft","pmids":["23113544"],"is_preprint":false},{"year":2013,"finding":"RNase-L promotes the innate immune response to intestinal damage and protects against experimental colitis and colitis-associated cancer. RNase-L(-/-) mice showed higher clinical scores, delayed leukocyte infiltration, reduced IFN-beta, TNF-alpha, IL-1beta, and IL-18, and increased tumor burden after DSS/AOM treatment. Bacterial RNA triggered IFN-beta production in an RNase-L-dependent manner.","method":"RNase-L(-/-) mice with DSS-induced colitis and DSS/AOM colitis-associated cancer model; histology; immunohistochemistry; cytokine qRT-PCR and ELISA; bacterial RNA stimulation","journal":"Inflammatory bowel diseases","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined phenotypes, multiple readouts, mechanistic link to bacterial RNA/IFN-beta pathway","pmids":["23567782"],"is_preprint":false},{"year":2016,"finding":"RNase-L binds to filamin A, an actin-binding protein, and this interaction maintains the cellular barrier to viral entry independently of RNase-L catalytic function. RNase-L also interacts with LNX (ligand of numb protein X), an E3 ubiquitin ligase and scaffolding protein that regulates tight junction proteins.","method":"Co-immunoprecipitation/pulldown; functional viral entry assays; catalytic mutant analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP/pulldown with functional viral entry readout; review article summarizing findings","pmids":["26760998"],"is_preprint":false},{"year":2016,"finding":"RNase-L promotes adipocyte differentiation by destabilizing Pref-1 mRNA, an inhibitor of adipogenesis. RNase-L knockdown increased Pref-1 mRNA levels and reduced 3T3-L1 adipocyte differentiation; Pref-1 mRNA was detected in RNase-L immunoprecipitates; elevated RNase-L ribonuclease activity increased Pref-1 mRNA decay rate. Downstream signaling via FAK, ERK, and SOX9 was activated by RNase-L suppression.","method":"RNase-L siRNA knockdown; mRNA profiling; RNase-L immunoprecipitation of mRNP complexes; mRNA decay assay; siRNA rescue experiment; meta-analysis of public array datasets; animal models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — direct mRNA substrate identification by IP, decay assay, KD/rescue with specific phenotype, in vivo confirmation","pmids":["27831565"],"is_preprint":false},{"year":2019,"finding":"Attenuation of CpG-high and UpA-high RNA viruses requires OAS3 and RNase L (but not OAS1), acting in synergy with ZAP. Knockout of RNase L or OAS3 reversed the attenuation of CpG- and UpA-high echovirus 7 mutants even in the presence of abundant ZAP, demonstrating complementarity/synergy between the ZAP and OAS3/RNase-L pathways.","method":"ZAP, RNase L, and OAS3 knockout cell lines; viral replication assays with CpG/UpA-high mutants; pulldown assays for ZAP-RNA interaction","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — KO cells with specific phenotype, multiple gene knockouts distinguishing OAS1 vs OAS3 pathway, reconstitution","pmids":["31276592"],"is_preprint":false},{"year":2014,"finding":"Two 2'-5' oligoadenylate molecules bridge ankyrin domains of two RNase L subunits bound in opposite orientations; binding of nucleotides to the pseudokinase domain further strengthens the dimer and imparts an active conformation to the ribonuclease domain.","method":"Structural analysis (referenced in review); biochemical studies of RNase L dimerization and activation","journal":"Virologie (Montrouge, France)","confidence":"Medium","confidence_rationale":"Tier 1 — structural finding, but cited through a review article without direct PMID for the primary structural paper in this corpus","pmids":["33065920"],"is_preprint":false},{"year":2022,"finding":"miR-146a-5p directly targets the 3'-UTR of RNASEL mRNA to repress RNase-L protein expression in melanoma cells, as demonstrated by luciferase reporter assay. miR-146a overexpression repressed RNase-L protein and activated ERK1/2, supporting a pro-tumorigenic role. Sex hormones differentially regulate RNase-L: 17β-estradiol increased RNase-L expression transcriptionally, while testosterone decreased it post-transcriptionally via a mechanism involving miR-146a.","method":"Luciferase reporter with RNASEL 3'-UTR; miR-146a mimic transfection; qPCR; western blot; hormone treatment experiments in LM-20 and A375 melanoma cell lines","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'-UTR targeting confirmed by reporter assay, protein-level validation; single lab","pmids":["36286041"],"is_preprint":false},{"year":2025,"finding":"RNase L activation by the OAS pathway leads to cell death upon tonic type I IFN induction. ADAR1p150 suppresses OAS-RNaseL pathway activation (in addition to MDA5 and PKR pathways) to prevent immune sensing of self-dsRNAs, with RNaseL acting downstream of IFN-induced OAS activation.","method":"Adar1 mutant mice rescued by MDA5 and PKR loss; IFNβ treatment of HSPCs in vitro; IFNAR1 neutralization in vivo; cell line experiments with OAS-RNaseL pathway activation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in vivo with defined phenotype; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.14.682456"],"is_preprint":true},{"year":2025,"finding":"RNase L activation upon dsRNA sensing inhibits NMD (nonsense-mediated decay) through translational blockade, creating a negative feedback loop that limits dsRNA sensing by reducing the dsRNA load and thus dampening IFN-beta induction, PKR and RNase L activation, and PIC-mediated cell death.","method":"RNaseL-deficient cell lines; PKR inhibition; NMD activity measurements; IFN-beta and ISG induction assays; dsRNA content measurements; IRF3 phosphorylation/translocation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — KO cells with multiple mechanistic readouts establishing feedback pathway; preprint","pmids":["bio_10.1101_2025.05.09.652687"],"is_preprint":true}],"current_model":"RNase L (RNASEL) is a 2-5A-dependent endoribonuclease that is activated when 2-5A binds to its ankyrin repeats 6-9 (inducing dimerization), enabling its ribonuclease domain to cleave single-stranded viral and cellular RNAs; it is the terminal effector of the OAS/RNase L innate immune pathway downstream of dsRNA sensing, mediating antiviral, antibacterial, proapoptotic, senescence-inducing, and antiproliferative activities, with its expression post-transcriptionally regulated by HuR (via 3'-UTR AREs) and miR-29/miR-146a, and its activity linked to cytoskeletal proteins (filamin A) and upstream regulators (NOD2/OAS2, BRCA1) that modulate its diverse cellular functions."},"narrative":{"teleology":[{"year":1999,"claim":"Defining the activation mechanism: the question of how 2-5A controls RNase L activity was resolved by showing that ankyrin repeats 6–9 serve as an autoinhibitory 2-5A-sensing module, while the C-terminal kinase-homology and ribonuclease domains are constitutively active when expressed alone.","evidence":"Domain truncation mutants expressed via vaccinia virus recombinants in cultured cells with functional activity comparison","pmids":["10090396"],"confidence":"High","gaps":["Atomic-resolution structure of 2-5A binding within ankyrin repeats not yet determined in this study","Dimerization mechanism not addressed"]},{"year":2002,"claim":"Establishing functional consequences of a disease-associated variant: the R462Q polymorphism was shown to reduce enzymatic activity approximately threefold, linking reduced RNase L function to hereditary prostate cancer susceptibility.","evidence":"In vitro enzymatic activity assay comparing wild-type and R462Q recombinant proteins","pmids":["12415269"],"confidence":"High","gaps":["Structural basis for reduced activity of R462Q not determined","Whether reduced activity alone is sufficient to drive tumorigenesis unclear"]},{"year":2004,"claim":"Demonstrating RNase L as a direct mediator of apoptosis: RNase L was shown to be required for apoptotic responses to 2-5A and topoisomerase I inhibitor/TRAIL, operating through JNK signaling, and its inhibitor RLI modulates this activity.","evidence":"Stable siRNA knockdown of RNase L in DU145 prostate cancer cells; apoptosis assays with multiple stimuli; JNK inhibitor experiments","pmids":["15604285"],"confidence":"High","gaps":["Direct JNK activation mechanism by RNase L not identified","Whether RNA cleavage products mediate JNK activation unknown"]},{"year":2004,"claim":"Revealing a non-canonical RNA substrate: RNase L was found to selectively regulate mitochondrial DNA-encoded mRNA stability without affecting nuclear-encoded transcripts, expanding its known substrate repertoire beyond viral RNA.","evidence":"RNase-L knockout vs. wild-type mouse embryo fibroblasts; actinomycin D chase; RNase-L overexpression","pmids":["15522195"],"confidence":"Medium","gaps":["Direct cleavage of mt-mRNAs by RNase L not demonstrated","Mechanism of selectivity for mt-mRNAs over nuclear mRNAs unknown","Single study without independent replication"]},{"year":2006,"claim":"Expanding RNase L biology to senescence and aging: RNase L was shown to induce cellular senescence in primary fibroblasts and apoptosis in transformed cells, with RNase-L-null mice living ~32% longer, establishing RNase L as a determinant of replicative lifespan.","evidence":"Ectopic expression, RNase-L knockout fibroblasts, 2-5A activation, SA-β-gal assays, BrdU incorporation, mouse lifespan studies","pmids":["17130839"],"confidence":"High","gaps":["Molecular targets whose cleavage triggers senescence not identified","Whether senescence function is separable from antiviral function unclear"]},{"year":2007,"claim":"Defining post-transcriptional control of RNASEL expression: HuR was identified as a stabilizer of RNASEL mRNA via binding to AU-rich elements 7 and 8 in the 3'-UTR, directly linking mRNA stability regulation to antiviral output.","evidence":"5'-RACE; chimeric reporter constructs; deletion analysis; HuR co-transfection; mRNA stability assays; HuR-RNase L mRNA co-IP; antiviral assays","pmids":["17237228"],"confidence":"High","gaps":["Signals that regulate HuR binding to RNASEL mRNA not defined","Whether other RNA-binding proteins compete at these AREs unknown"]},{"year":2008,"claim":"Establishing an antibacterial role: RNase-L-null mice showed dramatically increased mortality from B. anthracis and E. coli infection due to impaired proinflammatory cytokine induction and compromised endosomal bacterial killing via cathepsin E.","evidence":"RNase-L knockout mouse infection models; bacterial load quantification; cytokine measurements; cathepsin-E expression analysis","pmids":["19075243"],"confidence":"High","gaps":["Whether RNase L cleaves bacterial RNA directly in vivo not shown","Mechanism linking RNase L to cathepsin-E regulation not defined"]},{"year":2012,"claim":"Identifying miRNA-mediated regulation: the miR-29 family was shown to repress RNase L protein via four 3'-UTR target sites, and RNase L knockdown in CML cells inhibited proliferation, revealing a context-dependent oncogenic role.","evidence":"Luciferase reporter with RNASEL 3'-UTR; site mutagenesis; stable knockdown in K562 cells; xenograft tumor model","pmids":["23113544"],"confidence":"High","gaps":["How oncogenic and tumor-suppressive roles are reconciled across cancer types not resolved","Whether miR-29 regulation occurs in normal hematopoiesis unknown"]},{"year":2013,"claim":"Demonstrating a protective role in intestinal immunity: RNase L was required for innate immune responses to intestinal damage, protecting against colitis and colitis-associated cancer through IFN-β and proinflammatory cytokine production triggered by bacterial RNA.","evidence":"RNase-L knockout mice; DSS colitis and DSS/AOM cancer models; cytokine profiling; bacterial RNA stimulation","pmids":["23567782"],"confidence":"High","gaps":["Identity of specific bacterial RNA species sensed not determined","Role of RNase L in human IBD not established"]},{"year":2014,"claim":"Resolving the structural basis of activation: two 2-5A molecules were shown to bridge ankyrin domains of two RNase L subunits in opposite orientations, with pseudokinase domain nucleotide binding strengthening the dimer and activating the ribonuclease domain.","evidence":"Structural and biochemical studies of RNase L dimerization (cited through review)","pmids":["33065920"],"confidence":"Medium","gaps":["Primary structural data not directly available in this corpus","How dimerization is reversed during pathway downregulation not defined"]},{"year":2016,"claim":"Identifying a catalysis-independent function: RNase L was found to interact with filamin A to maintain cellular barriers against viral entry independently of its ribonuclease activity, demonstrating a non-enzymatic role.","evidence":"Co-immunoprecipitation/pulldown; viral entry assays; catalytic mutant analysis","pmids":["26760998"],"confidence":"Medium","gaps":["Structural basis of RNase L–filamin A interaction not determined","Whether other cytoskeletal partners contribute to barrier function unknown","Finding summarized in a review, primary data citation indirect"]},{"year":2016,"claim":"Demonstrating a role in adipocyte differentiation: RNase L was shown to directly bind and destabilize Pref-1 mRNA, an adipogenesis inhibitor, promoting differentiation through FAK/ERK/SOX9 signaling.","evidence":"siRNA knockdown; RNase L immunoprecipitation of Pref-1 mRNP; mRNA decay assay; rescue experiments; xenograft and animal models","pmids":["27831565"],"confidence":"High","gaps":["Whether 2-5A activation is required for Pref-1 cleavage not shown","Physiological signals activating RNase L during adipogenesis not identified"]},{"year":2019,"claim":"Delineating pathway specificity in antiviral defense: OAS3 (not OAS1) was established as the upstream activator of RNase L for restriction of CpG/UpA-high viruses, acting in synergy with the ZAP pathway.","evidence":"ZAP, RNase L, and OAS3 knockout cell lines; viral replication assays with CpG/UpA-modified echovirus 7 mutants","pmids":["31276592"],"confidence":"High","gaps":["Whether OAS3 specificity extends to other viral families not tested","Mechanism of ZAP–RNase L synergy at the molecular level not defined"]},{"year":2022,"claim":"Adding miR-146a as a second miRNA repressor and linking RNase L expression to hormonal regulation: miR-146a-5p directly targets the RNASEL 3'-UTR, and sex hormones differentially modulate RNase L levels through transcriptional (estradiol) and post-transcriptional (testosterone/miR-146a) mechanisms.","evidence":"Luciferase reporter; miR-146a mimic transfection; hormone treatment in melanoma cell lines; qPCR and western blot","pmids":["36286041"],"confidence":"Medium","gaps":["Hormonal regulation not confirmed outside melanoma","Whether miR-146a regulation contributes to sex differences in antiviral immunity not tested","Single lab study"]},{"year":null,"claim":"Key unresolved questions include how RNase L selects specific cellular mRNA substrates (mt-mRNAs, Pref-1) versus bulk RNA, the structural basis of its catalysis-independent barrier function through filamin A, and how its pro-apoptotic/senescence and context-dependent oncogenic activities are coordinated in different tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["No systematic identification of endogenous cleavage substrates across tissues","Structural model of RNase L–filamin A complex lacking","Mechanism reconciling tumor-suppressive and oncogenic roles unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,3,12,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,10,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,6,12]}],"complexes":[],"partners":["FLNA","HUR","OAS2","OAS3","LNX1"],"other_free_text":[]},"mechanistic_narrative":"RNASEL encodes a 2-5A-dependent endoribonuclease that serves as the terminal effector of the OAS innate immune pathway, cleaving single-stranded viral and cellular RNAs upon activation by 2',5'-oligoadenylates synthesized in response to double-stranded RNA. Binding of 2-5A to ankyrin repeats 6–9 induces RNase L dimerization and activation of its C-terminal ribonuclease domain, while the ankyrin repeats normally hold the enzyme in a latent state [PMID:10090396, PMID:33065920]. Beyond antiviral defense—where it synergizes with OAS3 and ZAP to restrict CpG/UpA-high viruses [PMID:31276592]—RNase L mediates antibacterial immunity by promoting proinflammatory cytokine production and bacterial clearance [PMID:19075243], induces apoptosis through JNK signaling [PMID:15604285], drives cellular senescence with consequences for organismal lifespan [PMID:17130839], promotes adipocyte differentiation by destabilizing Pref-1 mRNA [PMID:27831565], and maintains barrier function against viral entry through a catalysis-independent interaction with filamin A [PMID:26760998]. RNase L expression is post-transcriptionally regulated by HuR-mediated mRNA stabilization via 3'-UTR AU-rich elements and by miR-29 and miR-146a-mediated repression [PMID:17237228, PMID:23113544, PMID:36286041]."},"prefetch_data":{"uniprot":{"accession":"Q05823","full_name":"2-5A-dependent ribonuclease","aliases":["Ribonuclease 4","Ribonuclease L","RNase L"],"length_aa":741,"mass_kda":83.5,"function":"Endoribonuclease that functions in the interferon (IFN) antiviral response (PubMed:11585831, PubMed:26263979). In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes (PubMed:11585831, PubMed:26263979). RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis (PubMed:11585831, PubMed:26263979). Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances (PubMed:11585831, PubMed:26263979). In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis (PubMed:26263979). Might play a central role in the regulation of mRNA turnover (PubMed:11585831). Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length. Involved in intercellular immune signaling (PubMed:40010341). Cross-activated by 2',5'-oligoadenylates (2-5A) previously generated in RNA virus-infected cells, triggers type I interferon signaling in uninfected neighboring cells to limit local spread of infection (PubMed:40010341)","subcellular_location":"Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q05823/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNASEL","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNASEL","total_profiled":1310},"omim":[{"mim_id":"621409","title":"AUTOINFLAMMATION AND AUTOIMMUNITY, SYSTEMIC, WITH IMMUNE DYSREGULATION 2; AIAISD2","url":"https://www.omim.org/entry/621409"},{"mim_id":"618042","title":"IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA; IMD100","url":"https://www.omim.org/entry/618042"},{"mim_id":"609676","title":"MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN; MAVS","url":"https://www.omim.org/entry/609676"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"607057","title":"UBIQUITIN-SPECIFIC PROTEASE 18; USP18","url":"https://www.omim.org/entry/607057"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNASEL"},"hgnc":{"alias_symbol":[],"prev_symbol":["RNS4","PRCA1"]},"alphafold":{"accession":"Q05823","domains":[{"cath_id":"1.25.40.20","chopping":"22-239","consensus_level":"medium","plddt":97.0805,"start":22,"end":239},{"cath_id":"1.25.40.20","chopping":"240-331","consensus_level":"medium","plddt":95.4215,"start":240,"end":331},{"cath_id":"3.30.200.20","chopping":"356-437","consensus_level":"medium","plddt":96.8346,"start":356,"end":437},{"cath_id":"1.10.510.10","chopping":"441-446_459-587","consensus_level":"medium","plddt":94.5248,"start":441,"end":587},{"cath_id":"1.20.1440.180","chopping":"590-716","consensus_level":"high","plddt":93.1756,"start":590,"end":716}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05823","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q05823-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q05823-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNASEL","jax_strain_url":"https://www.jax.org/strain/search?query=RNASEL"},"sequence":{"accession":"Q05823","fasta_url":"https://rest.uniprot.org/uniprotkb/Q05823.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q05823/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05823"}},"corpus_meta":[{"pmid":"16609730","id":"PMC_16609730","title":"Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.","date":"2006","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/16609730","citation_count":452,"is_preprint":false},{"pmid":"12415269","id":"PMC_12415269","title":"RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases.","date":"2002","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12415269","citation_count":216,"is_preprint":false},{"pmid":"11941539","id":"PMC_11941539","title":"Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11941539","citation_count":165,"is_preprint":false},{"pmid":"12145743","id":"PMC_12145743","title":"A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews.","date":"2002","source":"American 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The protein kinase and ribonuclease domains (amino acids 340-741) are sufficient for constitutively active, 2-5A-unresponsive enzyme, demonstrating that ankyrin repeats act as key modulators of RNase L activity.\",\n      \"method\": \"Expression of truncated RNase L forms via vaccinia virus recombinants in cultured cells, with and without co-expression of 2-5A synthetase; functional activity comparison\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo reconstitution with domain truncation mutants, rigorous functional comparison\",\n      \"pmids\": [\"10090396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The RNASEL variant Arg462Gln has approximately three times less enzymatic (RNase) activity than the wild-type protein.\",\n      \"method\": \"Enzymatic activity assay comparing wild-type and R462Q variant proteins\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic activity assay; widely replicated across multiple independent studies\",\n      \"pmids\": [\"12415269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RNase L mediates apoptosis of prostate cancer cells in response to 2-5A, topoisomerase I inhibitor/TRAIL combination, and this apoptotic signaling involves c-Jun N-terminal kinase (JNK). RNase L-deficient DU145 cells were highly resistant to apoptosis from these stimuli, while knockdown of the RNase L inhibitor RLI (HP68) enhanced apoptosis.\",\n      \"method\": \"Stable siRNA knockdown of RNase L in DU145 prostate cancer cells; apoptosis assays with 2-5A, camptothecin/TRAIL combinations; JNK inhibitor experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific phenotypic readout, multiple orthogonal treatments, inhibitor validation of pathway\",\n      \"pmids\": [\"15604285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RNase L regulates the stability of mitochondrial DNA-encoded mRNAs (mt-mRNAs). In RNase-L-null mouse embryo fibroblasts, monensin-induced decrease in mt-mRNA half-life was reduced (>6h vs. 3h in wild-type), and induction of RNase-L further decreased mt-mRNA half-life to 1.5h. Nuclear-encoded beta-actin mRNA stability was unaffected.\",\n      \"method\": \"RNase-L(-/-) vs. wild-type mouse embryo fibroblasts; actinomycin D transcription termination assay; RNase-L overexpression in 3T3 fibroblasts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific phenotypic readout and OE confirmation, single study\",\n      \"pmids\": [\"15522195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRCA1 and STAT1 are required for IFN-gamma-induced transcriptional activation of 2,5-OAS, the upstream activator of RNase L, positioning BRCA1 as an upstream regulator of the OAS/RNase L apoptotic pathway. IFN-gamma-induced apoptosis was dependent on 2,5-OAS induction.\",\n      \"method\": \"Transient transfection of 2,5-OAS into breast cancer cell lines (colony growth/apoptosis assays); siRNA/dominant-negative BRCA1 and STAT1 knockdown; functional apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by KD with functional readout, single lab\",\n      \"pmids\": [\"15940267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNase L induces cellular senescence: ectopic expression of RNase L induced senescent morphology, decreased DNA synthesis, increased SA-β-galactosidase activity, and accelerated replicative senescence. RNase-L-null fibroblasts showed retarded senescence. Activation of endogenous RNase L by 2-5A induced senescence in parental WI38 fibroblasts but apoptosis in SV40-transformed cells. RNase-L(-/-) mice survived 31.7% longer than wild-type mice.\",\n      \"method\": \"Ectopic RNase L expression; RNase-L(-/-) vs. wild-type fibroblasts; 2-5A transfection; SA-β-gal assays; BrdU incorporation; mouse lifespan studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (OE, KO cells, KO mice, 2-5A activation), replicated across cell types\",\n      \"pmids\": [\"17130839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The 3'-UTR of RNASEL mRNA mediates post-transcriptional regulation of RNase L expression by decreasing mRNA stability. Eight AU-rich elements (AREs) were identified; AREs 7 and 8 serve a positive regulatory function. The RNA-binding protein HuR stabilizes RNase-L mRNA by binding within the region of AREs 7 and 8, enhancing RNase-L expression and antiviral activity.\",\n      \"method\": \"5'-RACE; chimeric beta-globin-3'-UTR reporter constructs; deletion analysis; HuR co-transfection; mRNA stability assays; immunoprecipitation of HuR-RNase-L mRNA complex; antiviral activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including reporter assays, mutagenesis/deletion, co-IP, and functional antiviral readout\",\n      \"pmids\": [\"17237228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RNase L is required for the antibacterial immune response. RNase-L(-/-) mice showed dramatically increased mortality after Bacillus anthracis and E. coli challenge due to increased bacterial load and compromised immune response. RNase-L is required for optimal induction of proinflammatory cytokines (TNF-alpha, IL-6, IL-12) and regulates cathepsin-E expression and endosome-associated activities that eliminate internalized bacteria.\",\n      \"method\": \"RNase-L(-/-) mouse infection models (B. anthracis, E. coli); bacterial load quantification; cytokine measurements; cathepsin-E expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined phenotype, multiple pathogens, multiple mechanistic readouts\",\n      \"pmids\": [\"19075243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NOD2 interacts with 2'-5'-oligoadenylate synthetase type 2 (OAS2), an upstream activator of RNase L. This interaction was confirmed by immunoprecipitation of endogenous OAS2 with NOD2 in THP-1 cells, and overexpression of NOD2 enhanced RNase-L activity in poly(I:C)-treated cells.\",\n      \"method\": \"Proteomics/pulldown; co-immunoprecipitation in HEK and THP-1 cells; RNase-L activity assay after NOD2 overexpression and poly(I:C) treatment\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal co-IP confirmed, functional RNase-L activity readout; single lab\",\n      \"pmids\": [\"19853919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The miR-29 family represses RNase-L protein expression via four target sites within the RNASEL 3'-UTR. In K562 CML cells, RNase-L knockdown inhibits proliferation in vitro and tumor growth in a xenograft model, revealing an oncogenic role for RNase-L in CML.\",\n      \"method\": \"Luciferase reporter with RNASEL 3'-UTR; site mutagenesis; stable RNase-L knockdown in K562 cells; in vitro proliferation assay; xenograft tumor model\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reporter + mutagenesis + functional KD in vitro and in vivo xenograft\",\n      \"pmids\": [\"23113544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNase-L promotes the innate immune response to intestinal damage and protects against experimental colitis and colitis-associated cancer. RNase-L(-/-) mice showed higher clinical scores, delayed leukocyte infiltration, reduced IFN-beta, TNF-alpha, IL-1beta, and IL-18, and increased tumor burden after DSS/AOM treatment. Bacterial RNA triggered IFN-beta production in an RNase-L-dependent manner.\",\n      \"method\": \"RNase-L(-/-) mice with DSS-induced colitis and DSS/AOM colitis-associated cancer model; histology; immunohistochemistry; cytokine qRT-PCR and ELISA; bacterial RNA stimulation\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined phenotypes, multiple readouts, mechanistic link to bacterial RNA/IFN-beta pathway\",\n      \"pmids\": [\"23567782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNase-L binds to filamin A, an actin-binding protein, and this interaction maintains the cellular barrier to viral entry independently of RNase-L catalytic function. RNase-L also interacts with LNX (ligand of numb protein X), an E3 ubiquitin ligase and scaffolding protein that regulates tight junction proteins.\",\n      \"method\": \"Co-immunoprecipitation/pulldown; functional viral entry assays; catalytic mutant analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP/pulldown with functional viral entry readout; review article summarizing findings\",\n      \"pmids\": [\"26760998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNase-L promotes adipocyte differentiation by destabilizing Pref-1 mRNA, an inhibitor of adipogenesis. RNase-L knockdown increased Pref-1 mRNA levels and reduced 3T3-L1 adipocyte differentiation; Pref-1 mRNA was detected in RNase-L immunoprecipitates; elevated RNase-L ribonuclease activity increased Pref-1 mRNA decay rate. Downstream signaling via FAK, ERK, and SOX9 was activated by RNase-L suppression.\",\n      \"method\": \"RNase-L siRNA knockdown; mRNA profiling; RNase-L immunoprecipitation of mRNP complexes; mRNA decay assay; siRNA rescue experiment; meta-analysis of public array datasets; animal models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct mRNA substrate identification by IP, decay assay, KD/rescue with specific phenotype, in vivo confirmation\",\n      \"pmids\": [\"27831565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Attenuation of CpG-high and UpA-high RNA viruses requires OAS3 and RNase L (but not OAS1), acting in synergy with ZAP. Knockout of RNase L or OAS3 reversed the attenuation of CpG- and UpA-high echovirus 7 mutants even in the presence of abundant ZAP, demonstrating complementarity/synergy between the ZAP and OAS3/RNase-L pathways.\",\n      \"method\": \"ZAP, RNase L, and OAS3 knockout cell lines; viral replication assays with CpG/UpA-high mutants; pulldown assays for ZAP-RNA interaction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO cells with specific phenotype, multiple gene knockouts distinguishing OAS1 vs OAS3 pathway, reconstitution\",\n      \"pmids\": [\"31276592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Two 2'-5' oligoadenylate molecules bridge ankyrin domains of two RNase L subunits bound in opposite orientations; binding of nucleotides to the pseudokinase domain further strengthens the dimer and imparts an active conformation to the ribonuclease domain.\",\n      \"method\": \"Structural analysis (referenced in review); biochemical studies of RNase L dimerization and activation\",\n      \"journal\": \"Virologie (Montrouge, France)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural finding, but cited through a review article without direct PMID for the primary structural paper in this corpus\",\n      \"pmids\": [\"33065920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-146a-5p directly targets the 3'-UTR of RNASEL mRNA to repress RNase-L protein expression in melanoma cells, as demonstrated by luciferase reporter assay. miR-146a overexpression repressed RNase-L protein and activated ERK1/2, supporting a pro-tumorigenic role. Sex hormones differentially regulate RNase-L: 17β-estradiol increased RNase-L expression transcriptionally, while testosterone decreased it post-transcriptionally via a mechanism involving miR-146a.\",\n      \"method\": \"Luciferase reporter with RNASEL 3'-UTR; miR-146a mimic transfection; qPCR; western blot; hormone treatment experiments in LM-20 and A375 melanoma cell lines\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting confirmed by reporter assay, protein-level validation; single lab\",\n      \"pmids\": [\"36286041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNase L activation by the OAS pathway leads to cell death upon tonic type I IFN induction. ADAR1p150 suppresses OAS-RNaseL pathway activation (in addition to MDA5 and PKR pathways) to prevent immune sensing of self-dsRNAs, with RNaseL acting downstream of IFN-induced OAS activation.\",\n      \"method\": \"Adar1 mutant mice rescued by MDA5 and PKR loss; IFNβ treatment of HSPCs in vitro; IFNAR1 neutralization in vivo; cell line experiments with OAS-RNaseL pathway activation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with defined phenotype; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682456\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNase L activation upon dsRNA sensing inhibits NMD (nonsense-mediated decay) through translational blockade, creating a negative feedback loop that limits dsRNA sensing by reducing the dsRNA load and thus dampening IFN-beta induction, PKR and RNase L activation, and PIC-mediated cell death.\",\n      \"method\": \"RNaseL-deficient cell lines; PKR inhibition; NMD activity measurements; IFN-beta and ISG induction assays; dsRNA content measurements; IRF3 phosphorylation/translocation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO cells with multiple mechanistic readouts establishing feedback pathway; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.05.09.652687\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RNase L (RNASEL) is a 2-5A-dependent endoribonuclease that is activated when 2-5A binds to its ankyrin repeats 6-9 (inducing dimerization), enabling its ribonuclease domain to cleave single-stranded viral and cellular RNAs; it is the terminal effector of the OAS/RNase L innate immune pathway downstream of dsRNA sensing, mediating antiviral, antibacterial, proapoptotic, senescence-inducing, and antiproliferative activities, with its expression post-transcriptionally regulated by HuR (via 3'-UTR AREs) and miR-29/miR-146a, and its activity linked to cytoskeletal proteins (filamin A) and upstream regulators (NOD2/OAS2, BRCA1) that modulate its diverse cellular functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RNASEL encodes a 2-5A-dependent endoribonuclease that serves as the terminal effector of the OAS innate immune pathway, cleaving single-stranded viral and cellular RNAs upon activation by 2',5'-oligoadenylates synthesized in response to double-stranded RNA. Binding of 2-5A to ankyrin repeats 6–9 induces RNase L dimerization and activation of its C-terminal ribonuclease domain, while the ankyrin repeats normally hold the enzyme in a latent state [PMID:10090396, PMID:33065920]. Beyond antiviral defense—where it synergizes with OAS3 and ZAP to restrict CpG/UpA-high viruses [PMID:31276592]—RNase L mediates antibacterial immunity by promoting proinflammatory cytokine production and bacterial clearance [PMID:19075243], induces apoptosis through JNK signaling [PMID:15604285], drives cellular senescence with consequences for organismal lifespan [PMID:17130839], promotes adipocyte differentiation by destabilizing Pref-1 mRNA [PMID:27831565], and maintains barrier function against viral entry through a catalysis-independent interaction with filamin A [PMID:26760998]. RNase L expression is post-transcriptionally regulated by HuR-mediated mRNA stabilization via 3'-UTR AU-rich elements and by miR-29 and miR-146a-mediated repression [PMID:17237228, PMID:23113544, PMID:36286041].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the activation mechanism: the question of how 2-5A controls RNase L activity was resolved by showing that ankyrin repeats 6–9 serve as an autoinhibitory 2-5A-sensing module, while the C-terminal kinase-homology and ribonuclease domains are constitutively active when expressed alone.\",\n      \"evidence\": \"Domain truncation mutants expressed via vaccinia virus recombinants in cultured cells with functional activity comparison\",\n      \"pmids\": [\"10090396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of 2-5A binding within ankyrin repeats not yet determined in this study\", \"Dimerization mechanism not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing functional consequences of a disease-associated variant: the R462Q polymorphism was shown to reduce enzymatic activity approximately threefold, linking reduced RNase L function to hereditary prostate cancer susceptibility.\",\n      \"evidence\": \"In vitro enzymatic activity assay comparing wild-type and R462Q recombinant proteins\",\n      \"pmids\": [\"12415269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for reduced activity of R462Q not determined\", \"Whether reduced activity alone is sufficient to drive tumorigenesis unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating RNase L as a direct mediator of apoptosis: RNase L was shown to be required for apoptotic responses to 2-5A and topoisomerase I inhibitor/TRAIL, operating through JNK signaling, and its inhibitor RLI modulates this activity.\",\n      \"evidence\": \"Stable siRNA knockdown of RNase L in DU145 prostate cancer cells; apoptosis assays with multiple stimuli; JNK inhibitor experiments\",\n      \"pmids\": [\"15604285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct JNK activation mechanism by RNase L not identified\", \"Whether RNA cleavage products mediate JNK activation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealing a non-canonical RNA substrate: RNase L was found to selectively regulate mitochondrial DNA-encoded mRNA stability without affecting nuclear-encoded transcripts, expanding its known substrate repertoire beyond viral RNA.\",\n      \"evidence\": \"RNase-L knockout vs. wild-type mouse embryo fibroblasts; actinomycin D chase; RNase-L overexpression\",\n      \"pmids\": [\"15522195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cleavage of mt-mRNAs by RNase L not demonstrated\", \"Mechanism of selectivity for mt-mRNAs over nuclear mRNAs unknown\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanding RNase L biology to senescence and aging: RNase L was shown to induce cellular senescence in primary fibroblasts and apoptosis in transformed cells, with RNase-L-null mice living ~32% longer, establishing RNase L as a determinant of replicative lifespan.\",\n      \"evidence\": \"Ectopic expression, RNase-L knockout fibroblasts, 2-5A activation, SA-β-gal assays, BrdU incorporation, mouse lifespan studies\",\n      \"pmids\": [\"17130839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets whose cleavage triggers senescence not identified\", \"Whether senescence function is separable from antiviral function unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining post-transcriptional control of RNASEL expression: HuR was identified as a stabilizer of RNASEL mRNA via binding to AU-rich elements 7 and 8 in the 3'-UTR, directly linking mRNA stability regulation to antiviral output.\",\n      \"evidence\": \"5'-RACE; chimeric reporter constructs; deletion analysis; HuR co-transfection; mRNA stability assays; HuR-RNase L mRNA co-IP; antiviral assays\",\n      \"pmids\": [\"17237228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that regulate HuR binding to RNASEL mRNA not defined\", \"Whether other RNA-binding proteins compete at these AREs unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing an antibacterial role: RNase-L-null mice showed dramatically increased mortality from B. anthracis and E. coli infection due to impaired proinflammatory cytokine induction and compromised endosomal bacterial killing via cathepsin E.\",\n      \"evidence\": \"RNase-L knockout mouse infection models; bacterial load quantification; cytokine measurements; cathepsin-E expression analysis\",\n      \"pmids\": [\"19075243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RNase L cleaves bacterial RNA directly in vivo not shown\", \"Mechanism linking RNase L to cathepsin-E regulation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying miRNA-mediated regulation: the miR-29 family was shown to repress RNase L protein via four 3'-UTR target sites, and RNase L knockdown in CML cells inhibited proliferation, revealing a context-dependent oncogenic role.\",\n      \"evidence\": \"Luciferase reporter with RNASEL 3'-UTR; site mutagenesis; stable knockdown in K562 cells; xenograft tumor model\",\n      \"pmids\": [\"23113544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How oncogenic and tumor-suppressive roles are reconciled across cancer types not resolved\", \"Whether miR-29 regulation occurs in normal hematopoiesis unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating a protective role in intestinal immunity: RNase L was required for innate immune responses to intestinal damage, protecting against colitis and colitis-associated cancer through IFN-β and proinflammatory cytokine production triggered by bacterial RNA.\",\n      \"evidence\": \"RNase-L knockout mice; DSS colitis and DSS/AOM cancer models; cytokine profiling; bacterial RNA stimulation\",\n      \"pmids\": [\"23567782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific bacterial RNA species sensed not determined\", \"Role of RNase L in human IBD not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving the structural basis of activation: two 2-5A molecules were shown to bridge ankyrin domains of two RNase L subunits in opposite orientations, with pseudokinase domain nucleotide binding strengthening the dimer and activating the ribonuclease domain.\",\n      \"evidence\": \"Structural and biochemical studies of RNase L dimerization (cited through review)\",\n      \"pmids\": [\"33065920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary structural data not directly available in this corpus\", \"How dimerization is reversed during pathway downregulation not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying a catalysis-independent function: RNase L was found to interact with filamin A to maintain cellular barriers against viral entry independently of its ribonuclease activity, demonstrating a non-enzymatic role.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown; viral entry assays; catalytic mutant analysis\",\n      \"pmids\": [\"26760998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of RNase L–filamin A interaction not determined\", \"Whether other cytoskeletal partners contribute to barrier function unknown\", \"Finding summarized in a review, primary data citation indirect\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating a role in adipocyte differentiation: RNase L was shown to directly bind and destabilize Pref-1 mRNA, an adipogenesis inhibitor, promoting differentiation through FAK/ERK/SOX9 signaling.\",\n      \"evidence\": \"siRNA knockdown; RNase L immunoprecipitation of Pref-1 mRNP; mRNA decay assay; rescue experiments; xenograft and animal models\",\n      \"pmids\": [\"27831565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 2-5A activation is required for Pref-1 cleavage not shown\", \"Physiological signals activating RNase L during adipogenesis not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Delineating pathway specificity in antiviral defense: OAS3 (not OAS1) was established as the upstream activator of RNase L for restriction of CpG/UpA-high viruses, acting in synergy with the ZAP pathway.\",\n      \"evidence\": \"ZAP, RNase L, and OAS3 knockout cell lines; viral replication assays with CpG/UpA-modified echovirus 7 mutants\",\n      \"pmids\": [\"31276592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OAS3 specificity extends to other viral families not tested\", \"Mechanism of ZAP–RNase L synergy at the molecular level not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Adding miR-146a as a second miRNA repressor and linking RNase L expression to hormonal regulation: miR-146a-5p directly targets the RNASEL 3'-UTR, and sex hormones differentially modulate RNase L levels through transcriptional (estradiol) and post-transcriptional (testosterone/miR-146a) mechanisms.\",\n      \"evidence\": \"Luciferase reporter; miR-146a mimic transfection; hormone treatment in melanoma cell lines; qPCR and western blot\",\n      \"pmids\": [\"36286041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hormonal regulation not confirmed outside melanoma\", \"Whether miR-146a regulation contributes to sex differences in antiviral immunity not tested\", \"Single lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how RNase L selects specific cellular mRNA substrates (mt-mRNAs, Pref-1) versus bulk RNA, the structural basis of its catalysis-independent barrier function through filamin A, and how its pro-apoptotic/senescence and context-dependent oncogenic activities are coordinated in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No systematic identification of endogenous cleavage substrates across tissues\", \"Structural model of RNase L–filamin A complex lacking\", \"Mechanism reconciling tumor-suppressive and oncogenic roles unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 3, 12, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 10, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FLNA\",\n      \"HuR\",\n      \"OAS2\",\n      \"OAS3\",\n      \"LNX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}