{"gene":"CFLAR","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1997,"finding":"I-FLICE (CFLAR) was cloned and characterized as a catalytically inert caspase-like protein that inhibits TNF receptor-1- and CD-95-induced apoptosis. It lacks both a catalytic active site and substrate binding pocket residues present in caspase-8/FLICE and caspase-10, consistent with a dominant-negative inhibitory function.","method":"Molecular cloning, sequence analysis, overexpression in mammalian cells with apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — molecular cloning with mutagenesis-informed structural analysis, functional inhibition assay, replicated across multiple contemporaneous papers identifying the same protein","pmids":["9211860"],"is_preprint":false},{"year":1997,"finding":"Casper (CFLAR) physically interacts with FADD, caspase-8, caspase-3, TRAF1, and TRAF2 through distinct domains. Overexpression induces apoptosis, while a C-terminal deletion mutant inhibits TNF- and Fas-induced cell death, placing CFLAR in the TNF-R1/Fas apoptotic pathway.","method":"Co-immunoprecipitation, overexpression and deletion mutant analysis in mammalian cells, apoptosis assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for multiple binding partners, deletion mutant functional analysis, replicated by independent labs in same year","pmids":["9208847"],"is_preprint":false},{"year":1997,"finding":"CLARP (CFLAR) contains two N-terminal death effector domains fused to a catalytically inactive caspase-like domain. It interacts with caspase-8 (but not FADD) and augments caspase-8/FADD-induced apoptosis. Its pro-apoptotic activity is blocked by the viral caspase inhibitor p35, dominant-negative caspase-8, and zVAD-fmk, placing it upstream of caspase activation.","method":"Sequence analysis, fluorogenic caspase activity assays, co-immunoprecipitation, overexpression with dominant-negative and pharmacological inhibitors in mammalian cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay confirming catalytic inactivity, Co-IP, epistasis via dominant-negative and inhibitor experiments, replicated across labs","pmids":["9380701"],"is_preprint":false},{"year":2000,"finding":"Casper (CFLAR)-deficient mice die by embryonic day 10.5 with impaired heart development, phenocopying FADD−/− and caspase-8−/− embryos. casper−/− embryonic fibroblasts are hypersensitive to FasL- and TNF-induced apoptosis with rapid caspase activation, but NF-κB and JNK/SAPK activation remains intact, establishing CFLAR as a cytoprotective regulator downstream of death receptors and as a developmental cooperator with FADD/caspase-8.","method":"Genetic knockout (casper−/− mice), cell death assays with FasL/TNF, caspase activity assays, NF-κB and JNK activation assays in embryonic fibroblasts","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean germline knockout with multiple orthogonal phenotypic readouts (embryonic lethality, apoptosis sensitivity, caspase activation, NF-κB/JNK signaling)","pmids":["10894163"],"is_preprint":false},{"year":1998,"finding":"RICK (RIP2) kinase physically interacts with CLARP (CFLAR) via its caspase-recruitment domain, and promotes caspase-8 activation and apoptosis induced by Fas ligand, FADD, CLARP, and caspase-8. A kinase-dead RICK mutant (K38M) functions as an inhibitor of CD95-mediated apoptosis, placing RICK as a kinase regulator upstream of CFLAR-mediated caspase-8 activation.","method":"Co-immunoprecipitation, deletion mutant analysis, kinase-dead mutant overexpression, apoptosis assays in mammalian cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, deletion mutant epistasis, kinase-dead dominant-negative; single lab","pmids":["9575181"],"is_preprint":false},{"year":2003,"finding":"Casper (CFLAR) physically interacts with NF-κB1 p105 through the C-terminal IκBγ domain of p105, as identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation. Overexpression of p105/IκBγ inhibits Casper-induced NF-κB activation and potentiates Casper-induced apoptosis. Additionally, Casper and its C-terminal caspase-like domain inhibit p105 processing into p50.","method":"Yeast two-hybrid screening, co-immunoprecipitation in 293 cells, overexpression assays, NF-κB reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP validation, functional NF-κB assays; single lab","pmids":["13679070"],"is_preprint":false},{"year":2005,"finding":"ASC-mediated NF-κB activation requires caspase-8 and is suppressed by CLARP/CFLAR. ASC recruits caspase-8 and CLARP (but not FADD) to speck-like aggregates. The catalytic activity of caspase-8 is required for ASC-mediated NF-κB activation at endogenous expression levels, placing CFLAR as an inhibitor of the ASC-caspase-8-NF-κB inflammatory signaling axis.","method":"siRNA knockdown, overexpression, co-immunoprecipitation, confocal microscopy of speck aggregates, NF-κB reporter assays, IL-8 ELISA in stable cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, imaging, reporter assay, cytokine measurement) in a single lab","pmids":["15701651"],"is_preprint":false},{"year":2005,"finding":"TRP53 (p53) modulates sensitivity to FAS-mediated apoptosis in germ cells by influencing CFLAR(L) protein stability: at the permissive p53 temperature, CFLAR(L) protein undergoes enhanced ubiquitinylation and degradation following FAS activation, whereas at non-permissive temperature CFLAR(L) accumulates. siRNA knockdown of Cflar at 37°C restored FAS-mediated apoptosis sensitivity, confirming CFLAR(L) as the effector of p53-regulated FAS resistance.","method":"Temperature-sensitive p53 cell line (GC-2spd), siRNA knockdown, Western blot for ubiquitination, real-time PCR, FAS agonistic antibody apoptosis assay","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with functional rescue, ubiquitination assay, temperature-switch epistasis; single lab","pmids":["16306425"],"is_preprint":false},{"year":2013,"finding":"CFLAR long isoform (CFLARL) plays a critical role in regulating autophagy, necroptosis, and apoptosis in T lymphocytes. CFLARL-deficient T cells undergo severe cell death upon TCR stimulation involving both apoptosis and necroptosis, and autophagy is enhanced in CFLARL-deficient T cells and plays a cytoprotective function.","method":"Genetic loss-of-function (CFLARL-deficient T cells), TCR stimulation assays, cell death pathway analysis (apoptosis/necroptosis), autophagy measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic loss-of-function with multiple pathway readouts; single lab, review/commentary format limits full method assessment","pmids":["23392074"],"is_preprint":false},{"year":2019,"finding":"PRMT5 stabilizes CFLARL protein by decreasing its ubiquitination and inhibiting its interaction with the E3 ubiquitin ligase ITCH, while PRMT1 promotes CFLARL degradation by enhancing ITCH binding and ubiquitination. Dead (catalytically inactive) mutants of PRMT5 and PRMT1 have the same effects as wild-type, indicating that physical interaction (not enzymatic activity) mediates regulation of CFLARL stability.","method":"Co-immunoprecipitation, GST pull-down, siRNA knockdown of PRMT1/PRMT5, HA-ubiquitin overexpression with proteasomal inhibitor treatment, Western blot in lung cancer cells","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, ubiquitination assay with catalytic-dead mutants; single lab","pmids":["30736843"],"is_preprint":false},{"year":2019,"finding":"GMEB1 interacts with CFLARL in the cytosol and promotes its stability by recruiting the deubiquitinase USP40, which performs K48-linked deubiquitination of CFLARL. USP40 knockdown abolishes GMEB1-mediated CFLARL stabilization. GMEB1 inhibits pro-caspase-8 activation and DISC formation upon TRAIL stimulation via CFLARL stabilization; CFLARL in turn enhances GMEB1-CASP8 binding.","method":"Co-immunoprecipitation, GST pull-down, immunofluorescence, siRNA knockdown, flow cytometry apoptosis assay, xenograft tumor model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, functional knockdown with apoptosis readout, in vivo xenograft; single lab","pmids":["31046799"],"is_preprint":false},{"year":2018,"finding":"Cigarette smoke exposure decreases CFLAR expression in bronchial epithelial cells and causes a shift in isoform balance toward c-FLIPS (consistent with necroptosis). siRNA-mediated downregulation of CFLAR in A549 cells increased baseline apoptosis and enhanced cigarette smoke extract-induced necrosis and DAMP release, establishing CFLAR as a gatekeeper against immunogenic cell death in airway epithelium.","method":"siRNA knockdown in A549 cells, apoptosis/necrosis assays, DAMP release measurement, bronchial biopsy expression analysis, isoform profiling in air-liquid interface cultures","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple cell death phenotype readouts (apoptosis, necrosis, DAMP); corroborated by in vivo biopsy data; single lab","pmids":["30127367"],"is_preprint":false},{"year":2019,"finding":"CFLAR activates CFLAR-JNK pathway signaling to suppress JNK phosphorylation; CFLAR knockdown (via adenovirus-mediated Cflar downregulation) exacerbated lipid accumulation and oxidative stress in hepatocytes, confirming CFLAR as a functional upstream regulator of JNK phosphorylation in the context of non-alcoholic steatohepatitis.","method":"Adenovirus-mediated Cflar knockdown in NCTC-1469 cells and MCD-diet mouse model, Western blot for pJNK/CFLAR, lipid accumulation assays, oxidative stress markers","journal":"Acta pharmaceutica Sinica. B","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primary readout is pharmacological (silibinin treatment), CFLAR loss-of-function is supporting; mechanism of CFLAR-JNK interaction not directly established","pmids":["31384535"],"is_preprint":false},{"year":2019,"finding":"CFLAR overexpression in mice subjected to middle cerebral artery occlusion (MCAO) reduced neurological deficit, brain water content, and infarct volume by suppressing NF-κB-mediated inflammation and ER stress markers (GRP78, PERK, ATF-6, cleaved Caspase-12). In vitro, CFLAR overexpression reduced OGD-induced cell death, while CFLAR knockdown accelerated caspase-3 cleavage in a manner reversed by ER stress blockade (4-PBA).","method":"Adenoviral CFLAR overexpression and siRNA knockdown in MCAO mouse model and OGD cell model, Western blot for NF-κB/ER stress markers, infarct volume measurement, caspase-3 cleavage assay","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss- and gain-of-function with phenotypic readouts but no direct biochemical demonstration of CFLAR-NF-κB or CFLAR-ER stress mechanism; single lab","pmids":["31387178"],"is_preprint":false}],"current_model":"CFLAR (c-FLIP) is a catalytically inactive caspase-8 paralog that contains two death effector domains and a caspase-like domain; it is recruited to death receptor signaling complexes where it interacts with FADD and caspase-8 to block apoptosis, while also regulating NF-κB activation, necroptosis, and autophagy, with its protein stability controlled by ubiquitin E3 ligase ITCH (opposed by deubiquitinase USP40 recruited via GMEB1) and modulated by PRMT1/PRMT5 through physical interactions that alter ITCH binding."},"narrative":{"mechanistic_narrative":"CFLAR (c-FLIP) is a catalytically inert caspase-8 paralog that functions as a central cytoprotective regulator of death receptor signaling, suppressing apoptosis triggered by TNF receptor-1 and Fas/CD95 [PMID:9211860, PMID:10894163]. It carries two N-terminal death effector domains fused to a caspase-like domain that lacks the catalytic active site and substrate-binding residues of caspase-8/FLICE [PMID:9211860, PMID:9380701], and it is recruited into death receptor signaling complexes through physical interactions with FADD and caspase-8 (as well as caspase-3, TRAF1, and TRAF2), positioning it upstream of caspase activation [PMID:9208847, PMID:9380701]. Genetic loss in mice causes embryonic lethality with impaired heart development that phenocopies FADD- and caspase-8-null embryos, and CFLAR-deficient fibroblasts are hypersensitive to FasL/TNF-induced apoptosis with rapid caspase activation while NF-κB and JNK signaling remain intact, establishing CFLAR as a death-receptor-downstream survival factor and developmental cooperator [PMID:10894163]. Beyond apoptosis, the long isoform CFLARL restrains necroptosis and autophagy, with deficiency in T lymphocytes provoking severe apoptotic and necroptotic death and enhanced cytoprotective autophagy [PMID:23392074]. CFLAR also modulates inflammatory NF-κB signaling, interacting with NF-κB1 p105 to inhibit its processing to p50 [PMID:13679070] and suppressing the ASC–caspase-8–NF-κB axis by being recruited with caspase-8 to ASC speck-like aggregates [PMID:15701651]. CFLARL abundance is tightly controlled by ubiquitin-dependent proteolysis: the E3 ligase ITCH drives its degradation, opposed by GMEB1-recruited deubiquitinase USP40 which removes K48-linked chains, while PRMT5 stabilizes and PRMT1 destabilizes the protein non-enzymatically by modulating ITCH binding [PMID:30736843, PMID:31046799].","teleology":[{"year":1997,"claim":"Established that CFLAR is a caspase-like protein that has lost catalytic function and instead acts as a dominant-negative inhibitor of death-receptor apoptosis, defining its core paradox of structure without enzymatic activity.","evidence":"Molecular cloning, sequence/active-site analysis, and overexpression apoptosis assays against TNF-R1 and CD95 in mammalian cells","pmids":["9211860","9380701"],"confidence":"High","gaps":["Did not resolve the molecular composition of the inhibitory complex at endogenous levels","Context-dependent pro- vs anti-apoptotic activity left unexplained"]},{"year":1997,"claim":"Mapped CFLAR's physical interactions to FADD, caspase-8, caspase-3, TRAF1 and TRAF2, placing it physically within the TNF-R1/Fas signaling complex.","evidence":"Reciprocal co-immunoprecipitation and deletion-mutant functional analysis in mammalian cells","pmids":["9208847","9380701"],"confidence":"High","gaps":["Overexpression yielded both pro- and anti-apoptotic outcomes, complicating physiological interpretation","Stoichiometry within the DISC not determined"]},{"year":1998,"claim":"Identified RICK/RIP2 as a kinase binding partner that couples CFLAR to caspase-8 activation, introducing a kinase-regulated input upstream of CFLAR function.","evidence":"Co-IP, deletion mutants, and kinase-dead (K38M) dominant-negative apoptosis assays","pmids":["9575181"],"confidence":"Medium","gaps":["Single lab, not independently confirmed","Physiological relevance of the RICK–CFLAR axis at endogenous levels untested"]},{"year":2000,"claim":"Demonstrated genetically that CFLAR is an essential cytoprotective regulator downstream of death receptors and a developmental cooperator with FADD/caspase-8, while sparing NF-κB/JNK signaling.","evidence":"casper−/− germline knockout mice with embryonic lethality, FasL/TNF apoptosis sensitivity, caspase activity and NF-κB/JNK assays in fibroblasts","pmids":["10894163"],"confidence":"High","gaps":["Did not separate apoptotic from non-apoptotic (necroptosis/autophagy) contributions to lethality","Isoform-specific roles not dissected"]},{"year":2003,"claim":"Connected CFLAR to NF-κB control by showing it binds NF-κB1 p105 and inhibits its processing to p50, linking apoptotic and inflammatory signaling at the protein level.","evidence":"Yeast two-hybrid, co-IP in 293 cells, and NF-κB reporter assays","pmids":["13679070"],"confidence":"Medium","gaps":["Single lab","Endogenous consequence on NF-κB target genes not established"]},{"year":2005,"claim":"Placed CFLAR as a suppressor of the ASC–caspase-8–NF-κB inflammatory axis, broadening its role beyond classical death receptors to inflammasome-associated signaling.","evidence":"siRNA, co-IP, confocal imaging of ASC specks, NF-κB reporter and IL-8 ELISA in stable cell lines","pmids":["15701651"],"confidence":"Medium","gaps":["Single lab","Mechanism by which CFLAR blocks caspase-8 catalytic output at specks undefined"]},{"year":2013,"claim":"Showed the long isoform CFLARL coordinately restrains apoptosis, necroptosis, and autophagy, establishing CFLAR as a multi-pathway cell-death gatekeeper rather than a pure apoptosis inhibitor.","evidence":"CFLARL-deficient T cells with TCR stimulation, cell-death pathway and autophagy readouts","pmids":["23392074"],"confidence":"Medium","gaps":["Single lab, commentary/review format limits method detail","Molecular basis of necroptosis and autophagy regulation not biochemically defined"]},{"year":2005,"claim":"Began defining how CFLAR protein levels are controlled, linking p53 to ubiquitin-dependent CFLARL degradation as a mechanism setting FAS apoptosis sensitivity.","evidence":"Temperature-sensitive p53 cell line, siRNA rescue, and ubiquitination Western blot with FAS agonist","pmids":["16306425"],"confidence":"Medium","gaps":["E3 ligase responsible not identified in this study","Single lab and cell type"]},{"year":2019,"claim":"Resolved the ubiquitin/deubiquitin axis controlling CFLARL stability, identifying ITCH as the degrading ligase opposed by GMEB1-recruited USP40 and modulated non-enzymatically by PRMT1/PRMT5.","evidence":"Co-IP, GST pull-down, siRNA, HA-ubiquitin assays with catalytic-dead PRMT mutants, and xenograft models in cancer cells","pmids":["30736843","31046799"],"confidence":"Medium","gaps":["Single lab for each axis","Whether PRMT methylation has any role beyond physical ITCH-binding modulation unresolved","Integration with p53-driven degradation not tested"]},{"year":2019,"claim":"Extended CFLAR's cytoprotective role to tissue-injury contexts (steatohepatitis, ischemic stroke, smoke-induced airway damage), linking it to JNK, NF-κB and ER-stress responses.","evidence":"Adenoviral gain/loss-of-function in hepatocyte, MCAO/OGD, and airway epithelial models with pathway markers","pmids":["31384535","31387178","30127367"],"confidence":"Low","gaps":["Direct biochemical mechanism of CFLAR–JNK and CFLAR–ER-stress links not established","Effects largely phenotypic and pharmacology-driven","Single lab per system"]},{"year":null,"claim":"How CFLAR isoform balance and post-translational regulation are integrated to switch cells between apoptosis, necroptosis, and autophagy across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the CFLAR-containing inhibitory complex at endogenous stoichiometry","Isoform-specific (CFLARL vs CFLARS) mechanisms not systematically separated","Cross-talk between p53, ITCH/USP40, and PRMT regulation of CFLAR stability untested in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,3,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8]}],"complexes":["DISC (death-inducing signaling complex)"],"partners":["FADD","CASP8","TRAF1","TRAF2","ITCH","USP40","GMEB1","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15519","full_name":"CASP8 and FADD-like apoptosis regulator","aliases":["Caspase homolog","CASH","Caspase-eight-related protein","Casper","Caspase-like apoptosis regulatory protein","CLARP","Cellular FLICE-like inhibitory protein","c-FLIP","FADD-like antiapoptotic molecule 1","FLAME-1","Inhibitor of FLICE","I-FLICE","MACH-related inducer of toxicity","MRIT","Usurpin"],"length_aa":480,"mass_kda":55.3,"function":"Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells (PubMed:31046799). Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O15519/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFLAR","classification":"Not Classified","n_dependent_lines":677,"n_total_lines":1208,"dependency_fraction":0.5604304635761589},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFLAR","total_profiled":1310},"omim":[{"mim_id":"617078","title":"DEATH EFFECTOR DOMAIN-CONTAINING PROTEIN 2; DEDD2","url":"https://www.omim.org/entry/617078"},{"mim_id":"612111","title":"TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 8; TNFAIP8","url":"https://www.omim.org/entry/612111"},{"mim_id":"606015","title":"FAS APOPTOTIC INHIBITORY MOLECULE 3; FAIM3","url":"https://www.omim.org/entry/606015"},{"mim_id":"605980","title":"NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1; NOD1","url":"https://www.omim.org/entry/605980"},{"mim_id":"605817","title":"RECEPTOR-INTERACTING SERINE/THREONINE KINASE 3; RIPK3","url":"https://www.omim.org/entry/605817"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CFLAR"},"hgnc":{"alias_symbol":["CASH","Casper","CLARP","FLAME","FLIP","I-FLICE","MRIT","c-FLIP","cFLIP"],"prev_symbol":["CASP8AP1"]},"alphafold":{"accession":"O15519","domains":[{"cath_id":"1.10.533.10","chopping":"4-91","consensus_level":"high","plddt":86.3287,"start":4,"end":91},{"cath_id":"1.10.533.10","chopping":"105-178","consensus_level":"high","plddt":83.7689,"start":105,"end":178},{"cath_id":"3.40.50.1460","chopping":"253-363_394-471","consensus_level":"high","plddt":91.8537,"start":253,"end":471}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15519","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15519-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15519-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFLAR","jax_strain_url":"https://www.jax.org/strain/search?query=CFLAR"},"sequence":{"accession":"O15519","fasta_url":"https://rest.uniprot.org/uniprotkb/O15519.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15519/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15519"}},"corpus_meta":[{"pmid":"21216670","id":"PMC_21216670","title":"Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial.","date":"2011","source":"The Lancet. 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Toxicology & pharmacology : CBP","url":"https://pubmed.ncbi.nlm.nih.gov/35227875","citation_count":10,"is_preprint":false},{"pmid":"36471522","id":"PMC_36471522","title":"Halogenated flame retardant exposure pathways in urban-adapted gulls: Are atmospheric routes underestimated?","date":"2022","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/36471522","citation_count":10,"is_preprint":false},{"pmid":"39167971","id":"PMC_39167971","title":"Cytotoxicity evaluation of organophosphorus flame retardants using electrochemical biosensors and elucidation of associated toxic mechanisms.","date":"2024","source":"Water research","url":"https://pubmed.ncbi.nlm.nih.gov/39167971","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52429,"output_tokens":4222,"usd":0.110309,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11914,"output_tokens":3779,"usd":0.077022,"stage2_stop_reason":"end_turn"},"total_usd":0.187331,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about CFLAR (also known as c-FLIP, CASH, Casper, CLARP, FLAME, I-FLICE, MRIT, cFLIP, CASP8AP1) - the apoptosis regulator protein.\n\nRelevant papers: [2], [3], [4], [6], [7], [31], [39], [43], [44], [53], [74], [9], [42], [52], [53], [56], [69]\n\nMost of the other papers are about flame retardant chemicals (a completely different meaning of \"FLAME\"), zebrafish \"casper\" strain (different gene), or bioinformatics tools named \"CASH\", \"CASPER\", \"FLAME\" - none of which are the CFLAR protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"I-FLICE (CFLAR) was cloned and characterized as a catalytically inert caspase-like protein that inhibits TNF receptor-1- and CD-95-induced apoptosis. It lacks both a catalytic active site and substrate binding pocket residues present in caspase-8/FLICE and caspase-10, consistent with a dominant-negative inhibitory function.\",\n      \"method\": \"Molecular cloning, sequence analysis, overexpression in mammalian cells with apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — molecular cloning with mutagenesis-informed structural analysis, functional inhibition assay, replicated across multiple contemporaneous papers identifying the same protein\",\n      \"pmids\": [\"9211860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Casper (CFLAR) physically interacts with FADD, caspase-8, caspase-3, TRAF1, and TRAF2 through distinct domains. Overexpression induces apoptosis, while a C-terminal deletion mutant inhibits TNF- and Fas-induced cell death, placing CFLAR in the TNF-R1/Fas apoptotic pathway.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and deletion mutant analysis in mammalian cells, apoptosis assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for multiple binding partners, deletion mutant functional analysis, replicated by independent labs in same year\",\n      \"pmids\": [\"9208847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CLARP (CFLAR) contains two N-terminal death effector domains fused to a catalytically inactive caspase-like domain. It interacts with caspase-8 (but not FADD) and augments caspase-8/FADD-induced apoptosis. Its pro-apoptotic activity is blocked by the viral caspase inhibitor p35, dominant-negative caspase-8, and zVAD-fmk, placing it upstream of caspase activation.\",\n      \"method\": \"Sequence analysis, fluorogenic caspase activity assays, co-immunoprecipitation, overexpression with dominant-negative and pharmacological inhibitors in mammalian cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay confirming catalytic inactivity, Co-IP, epistasis via dominant-negative and inhibitor experiments, replicated across labs\",\n      \"pmids\": [\"9380701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Casper (CFLAR)-deficient mice die by embryonic day 10.5 with impaired heart development, phenocopying FADD−/− and caspase-8−/− embryos. casper−/− embryonic fibroblasts are hypersensitive to FasL- and TNF-induced apoptosis with rapid caspase activation, but NF-κB and JNK/SAPK activation remains intact, establishing CFLAR as a cytoprotective regulator downstream of death receptors and as a developmental cooperator with FADD/caspase-8.\",\n      \"method\": \"Genetic knockout (casper−/− mice), cell death assays with FasL/TNF, caspase activity assays, NF-κB and JNK activation assays in embryonic fibroblasts\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean germline knockout with multiple orthogonal phenotypic readouts (embryonic lethality, apoptosis sensitivity, caspase activation, NF-κB/JNK signaling)\",\n      \"pmids\": [\"10894163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RICK (RIP2) kinase physically interacts with CLARP (CFLAR) via its caspase-recruitment domain, and promotes caspase-8 activation and apoptosis induced by Fas ligand, FADD, CLARP, and caspase-8. A kinase-dead RICK mutant (K38M) functions as an inhibitor of CD95-mediated apoptosis, placing RICK as a kinase regulator upstream of CFLAR-mediated caspase-8 activation.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis, kinase-dead mutant overexpression, apoptosis assays in mammalian cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, deletion mutant epistasis, kinase-dead dominant-negative; single lab\",\n      \"pmids\": [\"9575181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Casper (CFLAR) physically interacts with NF-κB1 p105 through the C-terminal IκBγ domain of p105, as identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation. Overexpression of p105/IκBγ inhibits Casper-induced NF-κB activation and potentiates Casper-induced apoptosis. Additionally, Casper and its C-terminal caspase-like domain inhibit p105 processing into p50.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation in 293 cells, overexpression assays, NF-κB reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP validation, functional NF-κB assays; single lab\",\n      \"pmids\": [\"13679070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ASC-mediated NF-κB activation requires caspase-8 and is suppressed by CLARP/CFLAR. ASC recruits caspase-8 and CLARP (but not FADD) to speck-like aggregates. The catalytic activity of caspase-8 is required for ASC-mediated NF-κB activation at endogenous expression levels, placing CFLAR as an inhibitor of the ASC-caspase-8-NF-κB inflammatory signaling axis.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation, confocal microscopy of speck aggregates, NF-κB reporter assays, IL-8 ELISA in stable cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, imaging, reporter assay, cytokine measurement) in a single lab\",\n      \"pmids\": [\"15701651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRP53 (p53) modulates sensitivity to FAS-mediated apoptosis in germ cells by influencing CFLAR(L) protein stability: at the permissive p53 temperature, CFLAR(L) protein undergoes enhanced ubiquitinylation and degradation following FAS activation, whereas at non-permissive temperature CFLAR(L) accumulates. siRNA knockdown of Cflar at 37°C restored FAS-mediated apoptosis sensitivity, confirming CFLAR(L) as the effector of p53-regulated FAS resistance.\",\n      \"method\": \"Temperature-sensitive p53 cell line (GC-2spd), siRNA knockdown, Western blot for ubiquitination, real-time PCR, FAS agonistic antibody apoptosis assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional rescue, ubiquitination assay, temperature-switch epistasis; single lab\",\n      \"pmids\": [\"16306425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CFLAR long isoform (CFLARL) plays a critical role in regulating autophagy, necroptosis, and apoptosis in T lymphocytes. CFLARL-deficient T cells undergo severe cell death upon TCR stimulation involving both apoptosis and necroptosis, and autophagy is enhanced in CFLARL-deficient T cells and plays a cytoprotective function.\",\n      \"method\": \"Genetic loss-of-function (CFLARL-deficient T cells), TCR stimulation assays, cell death pathway analysis (apoptosis/necroptosis), autophagy measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic loss-of-function with multiple pathway readouts; single lab, review/commentary format limits full method assessment\",\n      \"pmids\": [\"23392074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT5 stabilizes CFLARL protein by decreasing its ubiquitination and inhibiting its interaction with the E3 ubiquitin ligase ITCH, while PRMT1 promotes CFLARL degradation by enhancing ITCH binding and ubiquitination. Dead (catalytically inactive) mutants of PRMT5 and PRMT1 have the same effects as wild-type, indicating that physical interaction (not enzymatic activity) mediates regulation of CFLARL stability.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, siRNA knockdown of PRMT1/PRMT5, HA-ubiquitin overexpression with proteasomal inhibitor treatment, Western blot in lung cancer cells\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, ubiquitination assay with catalytic-dead mutants; single lab\",\n      \"pmids\": [\"30736843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GMEB1 interacts with CFLARL in the cytosol and promotes its stability by recruiting the deubiquitinase USP40, which performs K48-linked deubiquitination of CFLARL. USP40 knockdown abolishes GMEB1-mediated CFLARL stabilization. GMEB1 inhibits pro-caspase-8 activation and DISC formation upon TRAIL stimulation via CFLARL stabilization; CFLARL in turn enhances GMEB1-CASP8 binding.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, immunofluorescence, siRNA knockdown, flow cytometry apoptosis assay, xenograft tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, functional knockdown with apoptosis readout, in vivo xenograft; single lab\",\n      \"pmids\": [\"31046799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cigarette smoke exposure decreases CFLAR expression in bronchial epithelial cells and causes a shift in isoform balance toward c-FLIPS (consistent with necroptosis). siRNA-mediated downregulation of CFLAR in A549 cells increased baseline apoptosis and enhanced cigarette smoke extract-induced necrosis and DAMP release, establishing CFLAR as a gatekeeper against immunogenic cell death in airway epithelium.\",\n      \"method\": \"siRNA knockdown in A549 cells, apoptosis/necrosis assays, DAMP release measurement, bronchial biopsy expression analysis, isoform profiling in air-liquid interface cultures\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple cell death phenotype readouts (apoptosis, necrosis, DAMP); corroborated by in vivo biopsy data; single lab\",\n      \"pmids\": [\"30127367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CFLAR activates CFLAR-JNK pathway signaling to suppress JNK phosphorylation; CFLAR knockdown (via adenovirus-mediated Cflar downregulation) exacerbated lipid accumulation and oxidative stress in hepatocytes, confirming CFLAR as a functional upstream regulator of JNK phosphorylation in the context of non-alcoholic steatohepatitis.\",\n      \"method\": \"Adenovirus-mediated Cflar knockdown in NCTC-1469 cells and MCD-diet mouse model, Western blot for pJNK/CFLAR, lipid accumulation assays, oxidative stress markers\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primary readout is pharmacological (silibinin treatment), CFLAR loss-of-function is supporting; mechanism of CFLAR-JNK interaction not directly established\",\n      \"pmids\": [\"31384535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CFLAR overexpression in mice subjected to middle cerebral artery occlusion (MCAO) reduced neurological deficit, brain water content, and infarct volume by suppressing NF-κB-mediated inflammation and ER stress markers (GRP78, PERK, ATF-6, cleaved Caspase-12). In vitro, CFLAR overexpression reduced OGD-induced cell death, while CFLAR knockdown accelerated caspase-3 cleavage in a manner reversed by ER stress blockade (4-PBA).\",\n      \"method\": \"Adenoviral CFLAR overexpression and siRNA knockdown in MCAO mouse model and OGD cell model, Western blot for NF-κB/ER stress markers, infarct volume measurement, caspase-3 cleavage assay\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss- and gain-of-function with phenotypic readouts but no direct biochemical demonstration of CFLAR-NF-κB or CFLAR-ER stress mechanism; single lab\",\n      \"pmids\": [\"31387178\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFLAR (c-FLIP) is a catalytically inactive caspase-8 paralog that contains two death effector domains and a caspase-like domain; it is recruited to death receptor signaling complexes where it interacts with FADD and caspase-8 to block apoptosis, while also regulating NF-κB activation, necroptosis, and autophagy, with its protein stability controlled by ubiquitin E3 ligase ITCH (opposed by deubiquitinase USP40 recruited via GMEB1) and modulated by PRMT1/PRMT5 through physical interactions that alter ITCH binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFLAR (c-FLIP) is a catalytically inert caspase-8 paralog that functions as a central cytoprotective regulator of death receptor signaling, suppressing apoptosis triggered by TNF receptor-1 and Fas/CD95 [#0, #3]. It carries two N-terminal death effector domains fused to a caspase-like domain that lacks the catalytic active site and substrate-binding residues of caspase-8/FLICE [#0, #2], and it is recruited into death receptor signaling complexes through physical interactions with FADD and caspase-8 (as well as caspase-3, TRAF1, and TRAF2), positioning it upstream of caspase activation [#1, #2]. Genetic loss in mice causes embryonic lethality with impaired heart development that phenocopies FADD- and caspase-8-null embryos, and CFLAR-deficient fibroblasts are hypersensitive to FasL/TNF-induced apoptosis with rapid caspase activation while NF-\\u03baB and JNK signaling remain intact, establishing CFLAR as a death-receptor-downstream survival factor and developmental cooperator [#3]. Beyond apoptosis, the long isoform CFLARL restrains necroptosis and autophagy, with deficiency in T lymphocytes provoking severe apoptotic and necroptotic death and enhanced cytoprotective autophagy [#8]. CFLAR also modulates inflammatory NF-\\u03baB signaling, interacting with NF-\\u03baB1 p105 to inhibit its processing to p50 [#5] and suppressing the ASC\\u2013caspase-8\\u2013NF-\\u03baB axis by being recruited with caspase-8 to ASC speck-like aggregates [#6]. CFLARL abundance is tightly controlled by ubiquitin-dependent proteolysis: the E3 ligase ITCH drives its degradation, opposed by GMEB1-recruited deubiquitinase USP40 which removes K48-linked chains, while PRMT5 stabilizes and PRMT1 destabilizes the protein non-enzymatically by modulating ITCH binding [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that CFLAR is a caspase-like protein that has lost catalytic function and instead acts as a dominant-negative inhibitor of death-receptor apoptosis, defining its core paradox of structure without enzymatic activity.\",\n      \"evidence\": \"Molecular cloning, sequence/active-site analysis, and overexpression apoptosis assays against TNF-R1 and CD95 in mammalian cells\",\n      \"pmids\": [\"9211860\", \"9380701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular composition of the inhibitory complex at endogenous levels\", \"Context-dependent pro- vs anti-apoptotic activity left unexplained\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped CFLAR's physical interactions to FADD, caspase-8, caspase-3, TRAF1 and TRAF2, placing it physically within the TNF-R1/Fas signaling complex.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and deletion-mutant functional analysis in mammalian cells\",\n      \"pmids\": [\"9208847\", \"9380701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression yielded both pro- and anti-apoptotic outcomes, complicating physiological interpretation\", \"Stoichiometry within the DISC not determined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified RICK/RIP2 as a kinase binding partner that couples CFLAR to caspase-8 activation, introducing a kinase-regulated input upstream of CFLAR function.\",\n      \"evidence\": \"Co-IP, deletion mutants, and kinase-dead (K38M) dominant-negative apoptosis assays\",\n      \"pmids\": [\"9575181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently confirmed\", \"Physiological relevance of the RICK\\u2013CFLAR axis at endogenous levels untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated genetically that CFLAR is an essential cytoprotective regulator downstream of death receptors and a developmental cooperator with FADD/caspase-8, while sparing NF-\\u03baB/JNK signaling.\",\n      \"evidence\": \"casper\\u2212/\\u2212 germline knockout mice with embryonic lethality, FasL/TNF apoptosis sensitivity, caspase activity and NF-\\u03baB/JNK assays in fibroblasts\",\n      \"pmids\": [\"10894163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate apoptotic from non-apoptotic (necroptosis/autophagy) contributions to lethality\", \"Isoform-specific roles not dissected\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected CFLAR to NF-\\u03baB control by showing it binds NF-\\u03baB1 p105 and inhibits its processing to p50, linking apoptotic and inflammatory signaling at the protein level.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP in 293 cells, and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"13679070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Endogenous consequence on NF-\\u03baB target genes not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed CFLAR as a suppressor of the ASC\\u2013caspase-8\\u2013NF-\\u03baB inflammatory axis, broadening its role beyond classical death receptors to inflammasome-associated signaling.\",\n      \"evidence\": \"siRNA, co-IP, confocal imaging of ASC specks, NF-\\u03baB reporter and IL-8 ELISA in stable cell lines\",\n      \"pmids\": [\"15701651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which CFLAR blocks caspase-8 catalytic output at specks undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the long isoform CFLARL coordinately restrains apoptosis, necroptosis, and autophagy, establishing CFLAR as a multi-pathway cell-death gatekeeper rather than a pure apoptosis inhibitor.\",\n      \"evidence\": \"CFLARL-deficient T cells with TCR stimulation, cell-death pathway and autophagy readouts\",\n      \"pmids\": [\"23392074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, commentary/review format limits method detail\", \"Molecular basis of necroptosis and autophagy regulation not biochemically defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Began defining how CFLAR protein levels are controlled, linking p53 to ubiquitin-dependent CFLARL degradation as a mechanism setting FAS apoptosis sensitivity.\",\n      \"evidence\": \"Temperature-sensitive p53 cell line, siRNA rescue, and ubiquitination Western blot with FAS agonist\",\n      \"pmids\": [\"16306425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible not identified in this study\", \"Single lab and cell type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the ubiquitin/deubiquitin axis controlling CFLARL stability, identifying ITCH as the degrading ligase opposed by GMEB1-recruited USP40 and modulated non-enzymatically by PRMT1/PRMT5.\",\n      \"evidence\": \"Co-IP, GST pull-down, siRNA, HA-ubiquitin assays with catalytic-dead PRMT mutants, and xenograft models in cancer cells\",\n      \"pmids\": [\"30736843\", \"31046799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each axis\", \"Whether PRMT methylation has any role beyond physical ITCH-binding modulation unresolved\", \"Integration with p53-driven degradation not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CFLAR's cytoprotective role to tissue-injury contexts (steatohepatitis, ischemic stroke, smoke-induced airway damage), linking it to JNK, NF-\\u03baB and ER-stress responses.\",\n      \"evidence\": \"Adenoviral gain/loss-of-function in hepatocyte, MCAO/OGD, and airway epithelial models with pathway markers\",\n      \"pmids\": [\"31384535\", \"31387178\", \"30127367\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct biochemical mechanism of CFLAR\\u2013JNK and CFLAR\\u2013ER-stress links not established\", \"Effects largely phenotypic and pharmacology-driven\", \"Single lab per system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFLAR isoform balance and post-translational regulation are integrated to switch cells between apoptosis, necroptosis, and autophagy across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the CFLAR-containing inhibitory complex at endogenous stoichiometry\", \"Isoform-specific (CFLARL vs CFLARS) mechanisms not systematically separated\", \"Cross-talk between p53, ITCH/USP40, and PRMT regulation of CFLAR stability untested in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [\"DISC (death-inducing signaling complex)\"],\n    \"partners\": [\"FADD\", \"CASP8\", \"TRAF1\", \"TRAF2\", \"ITCH\", \"USP40\", \"GMEB1\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}