{"gene":"CASP1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1994,"finding":"The human CASP1 gene (IL1BC) encodes the IL-1β converting enzyme (ICE), a protease that proteolytically cleaves the inactive pro-form of IL-1β into biologically active IL-1β. The gene consists of 10 exons spanning at least 10.6 kb, maps to chromosome 11q22.2-q22.3, and has a single transcription start site ~33 bp upstream of the initiator Met codon.","method":"Genomic cloning, PCR-based transcription start site mapping, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular characterization of the gene and its protease function, foundational paper replicated broadly across the field","pmids":["8034320"],"is_preprint":false},{"year":1999,"finding":"In vivo intradermal transfer of CASP1 DNA into mouse skin demonstrates dual roles: CASP1 drives IL-1β-associated granulomatous inflammatory infiltration (suppressed by anti-IL-1β antibody) AND independently induces apoptotic cell death (TUNEL-positive cells persist after IL-1β neutralization), establishing CASP1 as both an IL-1β processor and a direct apoptosis inducer in vivo.","method":"Intradermal plasmid DNA transfer, TUNEL staining, neutralizing antibody treatment, plasma IL-1β measurement","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain-of-function with two orthogonal readouts (inflammation vs. apoptosis), single lab","pmids":["10468192"],"is_preprint":false},{"year":2015,"finding":"CASP1 cleaves the glucocorticoid receptor (GR), reducing GR protein levels and diminishing the glucocorticoid-induced transcriptional response. NLRP3 activates CASP1 in leukemia cells, and knockdown or pharmacological inhibition of CASP1 restores GR levels and reverses glucocorticoid resistance, establishing GR as a direct CASP1 substrate.","method":"CASP1 overexpression/knockdown in ALL cells, Western blot for GR cleavage, glucocorticoid transcriptional response assays, pharmacological CASP1 inhibition","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct cleavage of GR by CASP1 demonstrated in multiple ALL models with overexpression, knockdown, and inhibitor experiments, published in high-impact journal","pmids":["25938942"],"is_preprint":false},{"year":2017,"finding":"G9A (EHMT2) histone methyltransferase silences CASP1 expression by increasing H3K9me2 at the CASP1 promoter. Knockdown of G9A de-represses CASP1, and re-knockdown of CASP1 in G9A-deficient cells restores tumor invasion/migration capacity, placing CASP1 downstream of G9A-mediated epigenetic repression in NSCLC.","method":"shRNA knockdown, chromatin immunoprecipitation (ChIP) for H3K9me2, luciferase promoter assay, invasion/migration rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and epistasis rescue experiments in a single lab with multiple orthogonal methods","pmids":["28383547"],"is_preprint":false},{"year":2017,"finding":"Manganese (Mn) activates the NLRP3-CASP1 inflammasome in hippocampal microglia by inducing lysosomal damage and autophagy-lysosomal dysfunction; released lysosomal cathepsin B (CTSB) plays a key role in NLRP3-CASP1 activation. Increased autophagosomes were NOT the main cause of inflammasome activation.","method":"In vivo Mn exposure in mice, BV2 cell culture, CTSB inhibition, autophagy modulation, CASP1 activity assays, IL-1β/IL-18 ELISA","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection in vivo and in vitro with pharmacological intervention, single lab","pmids":["28318352"],"is_preprint":false},{"year":2019,"finding":"CASP1 variants (p.L265S, p.R240Q, and catalytic-site p.C285A) cause mutation-specific molecular alterations in macrophages including abnormal pyroptosome formation, impaired nuclear localization of pro-caspase-1 (for p.L265S), reduced pro-inflammatory cell death (for p.C285A), and changes in macrophage deformability, revealing scaffolding/localization roles of CASP1 beyond its catalytic activity.","method":"shRNA knockdown + viral transduction of CASP1 variants in THP-1 monocytes, immunofluorescence for subcellular localization, pyroptosome formation assay, deformability measurements","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple CASP1 variants tested with several functional readouts including localization and pyroptosome formation, single lab","pmids":["31252176"],"is_preprint":false},{"year":2020,"finding":"A CASP1 missense variant (p.R161H) is gain-of-function for both inflammasome activation and NF-κB signaling: patient PBMCs show increased caspase-1 activity, elevated IL-1β and IL-18 production upon NLRP3 stimulation, elevated IL-18 and IFNγ in whole blood, and the variant induces increased NF-κB activation in a RIP2-dependent manner in reporter assays.","method":"Whole exome sequencing, caspase-1 activity assay in patient PBMCs, cytokine ELISA, NF-κB luciferase reporter assay with CASP1 variant expression","journal":"Rheumatology (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of variant using multiple assays (enzymatic activity, cytokines, NF-κB reporter), single case but orthogonal methods","pmids":["32556329"],"is_preprint":false},{"year":2021,"finding":"PRMT5 (protein arginine methyltransferase 5) epigenetically silences CASP1 expression via H4R3me2s symmetric dimethylation; PRMT5 inhibition increases CASP1 expression and promotes pyroptosis in multiple myeloma cells, with CASP1 re-expression rescuing pyroptosis markers (N-GSDMD, IL-1β, IL-18) upon PRMT5 knockdown.","method":"PRMT5 knockdown/inhibition, rescue CASP1 expression, Western blot for pyroptosis markers, in vitro and in vivo phenotypic assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiments with in vivo validation, single lab","pmids":["34531375"],"is_preprint":false},{"year":2021,"finding":"NLRP3 and CASP1 expression and activity are modulated by intracellular Cl- concentration, with maximal expression and activity at 75 mM Cl-; this effect is mediated upstream by SGK1 kinase, which stimulates mature IL-1β secretion, which in turn autocrinally upregulates ROS, CASP1, NLRP3, and IL-1β itself. CASP1 inhibitor VX-765 and NLRP3 inhibitor MCC950 completely block Cl--stimulated IL-1β mRNA expression.","method":"Ionophore-induced Cl- modulation in epithelial cells, CASP1 inhibitor (VX-765), NLRP3 inhibitor (MCC950), SGK1 shRNA/inhibitor, ROS measurement, ELISA for IL-1β","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological and genetic dissection of upstream pathway regulation of CASP1, multiple inhibitors and shRNA used, single lab","pmids":["33835494"],"is_preprint":false},{"year":2023,"finding":"ATRA (all-trans-retinoic acid) activates CASP1 expression via the IFNγ/STAT1 signaling pathway in APL cells; activated CASP1 triggers pyroptosis and differentiation of APL cells, demonstrating CASP1 as a downstream effector of IFNγ/STAT1 in ATRA-induced APL cell death.","method":"CASP1 overexpression in APL cells, ATRA treatment, IFNγ/STAT1 pathway analysis, pyroptosis and differentiation assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway epistasis established by overexpression and pharmacological manipulation, single lab","pmids":["36822457"],"is_preprint":false},{"year":2024,"finding":"PRDM1 transcription factor directly activates CASP1 transcription (confirmed by ChIP and dual-luciferase reporter assay), promoting nucleus pulposus cell pyroptosis. CASP1 silencing reverses the effects of PRDM1 overexpression on pyroptosis, placing CASP1 directly downstream of PRDM1 transcriptional control.","method":"mRNA sequencing, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, CASP1 knockdown epistasis rescue, in vitro and in vivo models","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct promoter binding confirmed by ChIP and reporter assay with epistasis rescue, single lab","pmids":["39432156"],"is_preprint":false},{"year":2025,"finding":"Kynurenine directly binds CASP1 (confirmed by surface plasmon resonance) and reduces CASP1 cleavage, thereby suppressing pyroptosis in M2 macrophages. CASP1 overexpression reverses kynurenine-induced suppression of pyroptosis, establishing a direct inhibitory kynurenine-CASP1 interaction that promotes a tumor-supportive microenvironment in renal cell carcinoma.","method":"Surface plasmon resonance (direct binding), CASP1 overexpression rescue, VX-765 pharmacological inhibition, Transwell co-culture, pyroptosis assays","journal":"Open life sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding demonstrated by SPR plus overexpression rescue, single lab","pmids":["41079603"],"is_preprint":false},{"year":2026,"finding":"CASP1 functions as a scaffolding hub controlling NF-κB signaling in leukemia via interaction with raptor (RPTOR), a component of mTORC1, independent of its protease activity. Loss of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell growth; a PROTAC degrader of pro-CASP1 suppresses leukemic cells.","method":"CASP1 deletion/CARD domain disruption, co-IP of CASP1 with RPTOR, NF-κB activity assays, PROTAC degrader, in vivo leukemia burden assessment","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of CASP1-RPTOR interaction plus functional epistasis with CARD domain disruption and in vivo validation, single lab","pmids":["41500224"],"is_preprint":false},{"year":2022,"finding":"Co-immunoprecipitation confirmed that CASP1 is pulled down with NLRP3 in a reconstituted HEK293 inflammasome system (HEK293-iASC-NLRP3/CASP1), and ASC induction leads to increased cleaved/active CASP1; this complex formation is inhibited by MCC950, Glyburide, VX-765, and VRT-043198.","method":"Co-immunoprecipitation, doxycycline-inducible ASC expression system, fluorescence biosensor for CASP1 activity, flow cytometry, Western blot","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP in reconstituted system with multiple orthogonal readouts, single lab","pmids":["35221708"],"is_preprint":false},{"year":1998,"finding":"The rat Il1bc (CASP1 ortholog) gene was mapped to the centromeric region of rat chromosome 8, a region homologous to mouse chromosome 9, using linkage analysis in HXB and BXH recombinant inbred strains.","method":"Linkage analysis in recombinant inbred strains","journal":"Folia biologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic mapping only, no functional/mechanistic data, single study","pmids":["10730851"],"is_preprint":false}],"current_model":"CASP1 (caspase-1/ICE) is a cysteine protease that proteolytically processes pro-IL-1β and pro-IL-18 into their active forms and cleaves gasdermin D to execute pyroptosis; it is activated within multiprotein inflammasome complexes (e.g., NLRP3/ASC/CASP1) assembled in response to danger signals, regulated upstream by epigenetic writers (G9A, PRMT5) and transcription factors (PRDM1, IFNγ/STAT1), and—beyond its catalytic role—acts as a scaffolding hub interacting with RPTOR/mTORC1 to constrain NF-κB signaling; additionally, CASP1 cleaves non-canonical substrates including the glucocorticoid receptor, and gain-of-function CASP1 variants drive both inflammasome hyperactivation and RIP2-dependent NF-κB activation in autoinflammatory disease."},"narrative":{"mechanistic_narrative":"CASP1 (interleukin-1β converting enzyme/ICE) is a cysteine protease that drives inflammatory and cell-death programs by proteolytically maturing inflammatory cytokines and executing pyroptosis [PMID:8034320, PMID:34531375]. Within reconstituted inflammasome systems CASP1 is recruited into a complex with NLRP3 and ASC, where ASC induction promotes its autocatalytic activation [PMID:35221708]; activated CASP1 then processes pro-IL-1β and pro-IL-18 and cleaves gasdermin D, with re-expression of CASP1 restoring N-GSDMD, IL-1β and IL-18 generation [PMID:8034320, PMID:34531375]. Inflammasome engagement is triggered by upstream danger inputs including manganese-induced lysosomal damage and cathepsin B release [PMID:28318352] and intracellular chloride sensing through SGK1, which feeds an autocrine IL-1β amplification loop [PMID:33835494]. CASP1 expression is set by epigenetic and transcriptional regulators: the histone methyltransferases G9A/EHMT2 and PRMT5 silence the gene via H3K9me2 and H4R3me2s respectively [PMID:28383547, PMID:34531375], while PRDM1 and IFNγ/STAT1 signaling directly activate its transcription [PMID:36822457, PMID:39432156]. Beyond canonical cytokine substrates, CASP1 cleaves the glucocorticoid receptor to reduce GR levels and confer glucocorticoid resistance [PMID:25938942], and small metabolites such as kynurenine bind CASP1 directly to suppress its cleavage activity and dampen pyroptosis [PMID:41079603]. CASP1 also acts non-catalytically as a scaffold: through its CARD domain it interacts with RPTOR/mTORC1 to constrain NF-κB signaling, and loss or CARD disruption triggers excessive NF-κB activity [PMID:41500224]. Consistent with these dual roles, gain-of-function CASP1 variants drive both inflammasome hyperactivation and RIP2-dependent NF-κB activation in autoinflammatory disease, while other disease variants reveal scaffolding and subcellular-localization functions independent of catalysis [PMID:31252176, PMID:32556329].","teleology":[{"year":1994,"claim":"Established the molecular identity of CASP1 as the protease responsible for converting inactive pro-IL-1β into active IL-1β, defining its founding biochemical function.","evidence":"Genomic cloning, transcription start site mapping, and FISH localization of the human gene","pmids":["8034320"],"confidence":"High","gaps":["Did not resolve how the enzyme is activated in cells","No structural mechanism of substrate cleavage defined"]},{"year":1999,"claim":"Distinguished CASP1's IL-1β-processing inflammatory role from a separate capacity to directly induce cell death in vivo, hinting at functions beyond cytokine maturation.","evidence":"Intradermal plasmid transfer in mouse skin with TUNEL staining and anti-IL-1β neutralization","pmids":["10468192"],"confidence":"Medium","gaps":["Molecular pathway of the IL-1β-independent death was not defined","Single-lab in vivo gain-of-function"]},{"year":2015,"claim":"Identified the glucocorticoid receptor as a non-canonical CASP1 substrate, explaining how inflammasome activation can drive glucocorticoid resistance.","evidence":"CASP1 overexpression/knockdown and inhibition in ALL cells with GR cleavage and transcriptional readouts","pmids":["25938942"],"confidence":"High","gaps":["Cleavage site on GR not mapped","Generality beyond leukemia models untested"]},{"year":2017,"claim":"Showed CASP1 expression is epigenetically repressed by G9A-mediated H3K9me2 and that this repression supports tumor invasion, placing CASP1 under chromatin-level control.","evidence":"shRNA knockdown, ChIP, luciferase promoter assay, and invasion/migration rescue in NSCLC","pmids":["28383547"],"confidence":"Medium","gaps":["Whether de-repressed CASP1 acts catalytically or as scaffold here is unclear","Single-lab finding"]},{"year":2017,"claim":"Connected an environmental trigger to inflammasome activation by showing manganese activates NLRP3-CASP1 via lysosomal damage and cathepsin B release rather than autophagosome accumulation.","evidence":"In vivo Mn exposure plus BV2 microglia, CTSB inhibition, and CASP1 activity/cytokine assays","pmids":["28318352"],"confidence":"Medium","gaps":["Direct link between CTSB and CASP1 activation step not biochemically resolved","Single-lab study"]},{"year":2019,"claim":"Revealed that disease-associated CASP1 variants alter pyroptosome formation, nuclear localization, and cell mechanics, exposing scaffolding/localization roles independent of catalysis.","evidence":"Variant transduction in THP-1 monocytes with immunofluorescence, pyroptosome and deformability assays","pmids":["31252176"],"confidence":"Medium","gaps":["Mechanism linking nuclear localization to function unknown","Single-lab variant panel"]},{"year":2020,"claim":"Showed a gain-of-function CASP1 variant simultaneously hyperactivates the inflammasome and RIP2-dependent NF-κB signaling, tying CASP1 to autoinflammatory disease through two pathways.","evidence":"Whole exome sequencing, patient PBMC caspase-1 activity and cytokine assays, NF-κB reporter assays","pmids":["32556329"],"confidence":"Medium","gaps":["Single patient case","Direct mechanism of RIP2 engagement by CASP1 not defined"]},{"year":2021,"claim":"Extended epigenetic control of CASP1 to PRMT5-mediated H4R3me2s and demonstrated that relieving this silencing promotes pyroptosis, linking CASP1 re-expression to gasdermin/cytokine output.","evidence":"PRMT5 knockdown/inhibition with CASP1 rescue and pyroptosis marker Western blots in myeloma, with in vivo validation","pmids":["34531375"],"confidence":"Medium","gaps":["Whether PRMT5 acts solely at the CASP1 promoter not established","Single-lab finding"]},{"year":2021,"claim":"Identified intracellular chloride and SGK1 as upstream modulators of NLRP3-CASP1, defining an autocrine IL-1β amplification loop that reinforces inflammasome activity.","evidence":"Ionophore Cl- modulation in epithelial cells with VX-765, MCC950, SGK1 knockdown, and IL-1β/ROS measurements","pmids":["33835494"],"confidence":"Medium","gaps":["Direct chloride sensor for CASP1 not identified","Single-lab study"]},{"year":2022,"claim":"Provided reciprocal co-IP evidence that CASP1 physically associates with NLRP3 and is activated upon ASC nucleation in a reconstituted system, anchoring CASP1 within the inflammasome complex.","evidence":"Co-IP in HEK293-iASC-NLRP3/CASP1 cells with inducible ASC, activity biosensor, and inhibitor panel","pmids":["35221708"],"confidence":"Medium","gaps":["Stoichiometry and structure of the assembled complex not resolved","Reconstituted overexpression system"]},{"year":2023,"claim":"Placed CASP1 downstream of IFNγ/STAT1 signaling in ATRA-induced pyroptosis and differentiation of APL cells, defining a transcriptional activation route for CASP1.","evidence":"CASP1 overexpression and ATRA treatment in APL cells with pathway and pyroptosis/differentiation assays","pmids":["36822457"],"confidence":"Medium","gaps":["Direct STAT1 binding to CASP1 promoter not shown","Single-lab study"]},{"year":2024,"claim":"Demonstrated direct transcriptional activation of CASP1 by PRDM1 driving nucleus pulposus pyroptosis, completing a transcription-factor-level control node.","evidence":"mRNA-seq, ChIP, dual-luciferase reporter, and CASP1 knockdown epistasis with in vivo models","pmids":["39432156"],"confidence":"Medium","gaps":["Tissue-specificity of PRDM1-CASP1 regulation not explored","Single-lab finding"]},{"year":2025,"claim":"Showed kynurenine directly binds CASP1 to inhibit its cleavage activity, identifying a metabolite-level brake on pyroptosis that shapes the tumor microenvironment.","evidence":"Surface plasmon resonance binding, CASP1 overexpression rescue, and VX-765 inhibition in M2 macrophages/RCC co-culture","pmids":["41079603"],"confidence":"Medium","gaps":["Binding site on CASP1 not mapped","Single-lab study"]},{"year":2026,"claim":"Defined a protease-independent scaffolding role for CASP1, where its CARD domain interacts with RPTOR/mTORC1 to restrain NF-κB and support leukemic growth.","evidence":"CASP1 deletion/CARD disruption, CASP1-RPTOR co-IP, NF-κB assays, and a pro-CASP1 PROTAC degrader with in vivo leukemia models","pmids":["41500224"],"confidence":"Medium","gaps":["Structural basis of CASP1-RPTOR interaction unresolved","How scaffolding suppresses NF-κB mechanistically not detailed"]},{"year":null,"claim":"How CASP1's catalytic, pro-death, and scaffolding/RPTOR functions are partitioned and coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating CARD-scaffolding and protease states","Switch between cytokine maturation, GR cleavage, and NF-κB control not defined","Physiological substrate repertoire beyond IL-1β/IL-18/GSDMD/GR incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,7,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,13,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,6]}],"complexes":["NLRP3 inflammasome"],"partners":["NLRP3","ASC","RPTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P29466","full_name":"Caspase-1","aliases":["Interleukin-1 beta convertase","IL-1BC","Interleukin-1 beta-converting enzyme","ICE","IL-1 beta-converting enzyme","p45"],"length_aa":404,"mass_kda":45.2,"function":"Thiol protease involved in a variety of inflammatory processes by proteolytically cleaving other proteins, such as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18 (IL18) as well as the pyroptosis inducer Gasdermin-D (GSDMD), into active mature peptides (PubMed:15326478, PubMed:15498465, PubMed:1574116, PubMed:26375003, PubMed:32051255, PubMed:37993714, PubMed:7876192, PubMed:9334240). Plays a key role in cell immunity as an inflammatory response initiator: once activated through formation of an inflammasome complex, it initiates a pro-inflammatory response through the cleavage of the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines which are involved in a variety of inflammatory processes (PubMed:15326478, PubMed:15498465, PubMed:1574116, PubMed:32051255, PubMed:7876192). Cleaves a tetrapeptide after an Asp residue at position P1 (PubMed:15498465, PubMed:1574116, PubMed:7876192). Also initiates pyroptosis, a programmed lytic cell death pathway, through cleavage of GSDMD (PubMed:26375003). In contrast to cleavage of interleukin IL1B, recognition and cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32051255, PubMed:32109412, PubMed:32553275). Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair (PubMed:22464733). Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive (PubMed:28314590). In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly (PubMed:20197547) Apoptosis inactive Apoptosis inactive","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P29466/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASP1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CASP1","total_profiled":1310},"omim":[{"mim_id":"619558","title":"RAB39A, MEMBER RAS ONCOGENE FAMILY; RAB39A","url":"https://www.omim.org/entry/619558"},{"mim_id":"617042","title":"GASDERMIN D; GSDMD","url":"https://www.omim.org/entry/617042"},{"mim_id":"616115","title":"FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 4; FCAS4","url":"https://www.omim.org/entry/616115"},{"mim_id":"616050","title":"AUTOINFLAMMATION WITH INFANTILE ENTEROCOLITIS; AIFEC","url":"https://www.omim.org/entry/616050"},{"mim_id":"615701","title":"PYRIN DOMAIN-CONTAINING PROTEIN 2; PYDC2","url":"https://www.omim.org/entry/615701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":122.0},{"tissue":"lymphoid tissue","ntpm":87.0}],"url":"https://www.proteinatlas.org/search/CASP1"},"hgnc":{"alias_symbol":["ICE"],"prev_symbol":["IL1BC"]},"alphafold":{"accession":"P29466","domains":[{"cath_id":"1.10.533.10","chopping":"3-88","consensus_level":"high","plddt":86.4373,"start":3,"end":88},{"cath_id":"3.40.50.1460","chopping":"139-289_319-391","consensus_level":"high","plddt":91.5701,"start":139,"end":391}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29466","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29466-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29466-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASP1","jax_strain_url":"https://www.jax.org/strain/search?query=CASP1"},"sequence":{"accession":"P29466","fasta_url":"https://rest.uniprot.org/uniprotkb/P29466.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29466/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29466"}},"corpus_meta":[{"pmid":"28318352","id":"PMC_28318352","title":"The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability.","date":"2017","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/28318352","citation_count":191,"is_preprint":false},{"pmid":"25938942","id":"PMC_25938942","title":"NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25938942","citation_count":140,"is_preprint":false},{"pmid":"28383547","id":"PMC_28383547","title":"G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28383547","citation_count":66,"is_preprint":false},{"pmid":"33065089","id":"PMC_33065089","title":"Long noncoding RNA MIAT regulates primary human retinal pericyte pyroptosis by modulating miR-342-3p targeting of CASP1 in diabetic retinopathy.","date":"2020","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/33065089","citation_count":55,"is_preprint":false},{"pmid":"22151792","id":"PMC_22151792","title":"The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles.","date":"2011","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/22151792","citation_count":52,"is_preprint":false},{"pmid":"8034320","id":"PMC_8034320","title":"Molecular characterization of the gene for human interleukin-1 beta converting enzyme (IL1BC).","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8034320","citation_count":44,"is_preprint":false},{"pmid":"29592872","id":"PMC_29592872","title":"The long non-coding RNA SNHG5 regulates gefitinib resistance in lung adenocarcinoma cells by targetting miR-377/CASP1 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The gene consists of 10 exons spanning at least 10.6 kb, maps to chromosome 11q22.2-q22.3, and has a single transcription start site ~33 bp upstream of the initiator Met codon.\",\n      \"method\": \"Genomic cloning, PCR-based transcription start site mapping, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular characterization of the gene and its protease function, foundational paper replicated broadly across the field\",\n      \"pmids\": [\"8034320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In vivo intradermal transfer of CASP1 DNA into mouse skin demonstrates dual roles: CASP1 drives IL-1β-associated granulomatous inflammatory infiltration (suppressed by anti-IL-1β antibody) AND independently induces apoptotic cell death (TUNEL-positive cells persist after IL-1β neutralization), establishing CASP1 as both an IL-1β processor and a direct apoptosis inducer in vivo.\",\n      \"method\": \"Intradermal plasmid DNA transfer, TUNEL staining, neutralizing antibody treatment, plasma IL-1β measurement\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain-of-function with two orthogonal readouts (inflammation vs. apoptosis), single lab\",\n      \"pmids\": [\"10468192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CASP1 cleaves the glucocorticoid receptor (GR), reducing GR protein levels and diminishing the glucocorticoid-induced transcriptional response. NLRP3 activates CASP1 in leukemia cells, and knockdown or pharmacological inhibition of CASP1 restores GR levels and reverses glucocorticoid resistance, establishing GR as a direct CASP1 substrate.\",\n      \"method\": \"CASP1 overexpression/knockdown in ALL cells, Western blot for GR cleavage, glucocorticoid transcriptional response assays, pharmacological CASP1 inhibition\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct cleavage of GR by CASP1 demonstrated in multiple ALL models with overexpression, knockdown, and inhibitor experiments, published in high-impact journal\",\n      \"pmids\": [\"25938942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"G9A (EHMT2) histone methyltransferase silences CASP1 expression by increasing H3K9me2 at the CASP1 promoter. Knockdown of G9A de-represses CASP1, and re-knockdown of CASP1 in G9A-deficient cells restores tumor invasion/migration capacity, placing CASP1 downstream of G9A-mediated epigenetic repression in NSCLC.\",\n      \"method\": \"shRNA knockdown, chromatin immunoprecipitation (ChIP) for H3K9me2, luciferase promoter assay, invasion/migration rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and epistasis rescue experiments in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28383547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Manganese (Mn) activates the NLRP3-CASP1 inflammasome in hippocampal microglia by inducing lysosomal damage and autophagy-lysosomal dysfunction; released lysosomal cathepsin B (CTSB) plays a key role in NLRP3-CASP1 activation. Increased autophagosomes were NOT the main cause of inflammasome activation.\",\n      \"method\": \"In vivo Mn exposure in mice, BV2 cell culture, CTSB inhibition, autophagy modulation, CASP1 activity assays, IL-1β/IL-18 ELISA\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection in vivo and in vitro with pharmacological intervention, single lab\",\n      \"pmids\": [\"28318352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CASP1 variants (p.L265S, p.R240Q, and catalytic-site p.C285A) cause mutation-specific molecular alterations in macrophages including abnormal pyroptosome formation, impaired nuclear localization of pro-caspase-1 (for p.L265S), reduced pro-inflammatory cell death (for p.C285A), and changes in macrophage deformability, revealing scaffolding/localization roles of CASP1 beyond its catalytic activity.\",\n      \"method\": \"shRNA knockdown + viral transduction of CASP1 variants in THP-1 monocytes, immunofluorescence for subcellular localization, pyroptosome formation assay, deformability measurements\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple CASP1 variants tested with several functional readouts including localization and pyroptosome formation, single lab\",\n      \"pmids\": [\"31252176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A CASP1 missense variant (p.R161H) is gain-of-function for both inflammasome activation and NF-κB signaling: patient PBMCs show increased caspase-1 activity, elevated IL-1β and IL-18 production upon NLRP3 stimulation, elevated IL-18 and IFNγ in whole blood, and the variant induces increased NF-κB activation in a RIP2-dependent manner in reporter assays.\",\n      \"method\": \"Whole exome sequencing, caspase-1 activity assay in patient PBMCs, cytokine ELISA, NF-κB luciferase reporter assay with CASP1 variant expression\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of variant using multiple assays (enzymatic activity, cytokines, NF-κB reporter), single case but orthogonal methods\",\n      \"pmids\": [\"32556329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 (protein arginine methyltransferase 5) epigenetically silences CASP1 expression via H4R3me2s symmetric dimethylation; PRMT5 inhibition increases CASP1 expression and promotes pyroptosis in multiple myeloma cells, with CASP1 re-expression rescuing pyroptosis markers (N-GSDMD, IL-1β, IL-18) upon PRMT5 knockdown.\",\n      \"method\": \"PRMT5 knockdown/inhibition, rescue CASP1 expression, Western blot for pyroptosis markers, in vitro and in vivo phenotypic assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiments with in vivo validation, single lab\",\n      \"pmids\": [\"34531375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP3 and CASP1 expression and activity are modulated by intracellular Cl- concentration, with maximal expression and activity at 75 mM Cl-; this effect is mediated upstream by SGK1 kinase, which stimulates mature IL-1β secretion, which in turn autocrinally upregulates ROS, CASP1, NLRP3, and IL-1β itself. CASP1 inhibitor VX-765 and NLRP3 inhibitor MCC950 completely block Cl--stimulated IL-1β mRNA expression.\",\n      \"method\": \"Ionophore-induced Cl- modulation in epithelial cells, CASP1 inhibitor (VX-765), NLRP3 inhibitor (MCC950), SGK1 shRNA/inhibitor, ROS measurement, ELISA for IL-1β\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological and genetic dissection of upstream pathway regulation of CASP1, multiple inhibitors and shRNA used, single lab\",\n      \"pmids\": [\"33835494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATRA (all-trans-retinoic acid) activates CASP1 expression via the IFNγ/STAT1 signaling pathway in APL cells; activated CASP1 triggers pyroptosis and differentiation of APL cells, demonstrating CASP1 as a downstream effector of IFNγ/STAT1 in ATRA-induced APL cell death.\",\n      \"method\": \"CASP1 overexpression in APL cells, ATRA treatment, IFNγ/STAT1 pathway analysis, pyroptosis and differentiation assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway epistasis established by overexpression and pharmacological manipulation, single lab\",\n      \"pmids\": [\"36822457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDM1 transcription factor directly activates CASP1 transcription (confirmed by ChIP and dual-luciferase reporter assay), promoting nucleus pulposus cell pyroptosis. CASP1 silencing reverses the effects of PRDM1 overexpression on pyroptosis, placing CASP1 directly downstream of PRDM1 transcriptional control.\",\n      \"method\": \"mRNA sequencing, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, CASP1 knockdown epistasis rescue, in vitro and in vivo models\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct promoter binding confirmed by ChIP and reporter assay with epistasis rescue, single lab\",\n      \"pmids\": [\"39432156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Kynurenine directly binds CASP1 (confirmed by surface plasmon resonance) and reduces CASP1 cleavage, thereby suppressing pyroptosis in M2 macrophages. CASP1 overexpression reverses kynurenine-induced suppression of pyroptosis, establishing a direct inhibitory kynurenine-CASP1 interaction that promotes a tumor-supportive microenvironment in renal cell carcinoma.\",\n      \"method\": \"Surface plasmon resonance (direct binding), CASP1 overexpression rescue, VX-765 pharmacological inhibition, Transwell co-culture, pyroptosis assays\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding demonstrated by SPR plus overexpression rescue, single lab\",\n      \"pmids\": [\"41079603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CASP1 functions as a scaffolding hub controlling NF-κB signaling in leukemia via interaction with raptor (RPTOR), a component of mTORC1, independent of its protease activity. Loss of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell growth; a PROTAC degrader of pro-CASP1 suppresses leukemic cells.\",\n      \"method\": \"CASP1 deletion/CARD domain disruption, co-IP of CASP1 with RPTOR, NF-κB activity assays, PROTAC degrader, in vivo leukemia burden assessment\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of CASP1-RPTOR interaction plus functional epistasis with CARD domain disruption and in vivo validation, single lab\",\n      \"pmids\": [\"41500224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Co-immunoprecipitation confirmed that CASP1 is pulled down with NLRP3 in a reconstituted HEK293 inflammasome system (HEK293-iASC-NLRP3/CASP1), and ASC induction leads to increased cleaved/active CASP1; this complex formation is inhibited by MCC950, Glyburide, VX-765, and VRT-043198.\",\n      \"method\": \"Co-immunoprecipitation, doxycycline-inducible ASC expression system, fluorescence biosensor for CASP1 activity, flow cytometry, Western blot\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP in reconstituted system with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"35221708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The rat Il1bc (CASP1 ortholog) gene was mapped to the centromeric region of rat chromosome 8, a region homologous to mouse chromosome 9, using linkage analysis in HXB and BXH recombinant inbred strains.\",\n      \"method\": \"Linkage analysis in recombinant inbred strains\",\n      \"journal\": \"Folia biologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic mapping only, no functional/mechanistic data, single study\",\n      \"pmids\": [\"10730851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASP1 (caspase-1/ICE) is a cysteine protease that proteolytically processes pro-IL-1β and pro-IL-18 into their active forms and cleaves gasdermin D to execute pyroptosis; it is activated within multiprotein inflammasome complexes (e.g., NLRP3/ASC/CASP1) assembled in response to danger signals, regulated upstream by epigenetic writers (G9A, PRMT5) and transcription factors (PRDM1, IFNγ/STAT1), and—beyond its catalytic role—acts as a scaffolding hub interacting with RPTOR/mTORC1 to constrain NF-κB signaling; additionally, CASP1 cleaves non-canonical substrates including the glucocorticoid receptor, and gain-of-function CASP1 variants drive both inflammasome hyperactivation and RIP2-dependent NF-κB activation in autoinflammatory disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CASP1 (interleukin-1β converting enzyme/ICE) is a cysteine protease that drives inflammatory and cell-death programs by proteolytically maturing inflammatory cytokines and executing pyroptosis [#0, #7]. Within reconstituted inflammasome systems CASP1 is recruited into a complex with NLRP3 and ASC, where ASC induction promotes its autocatalytic activation [#13]; activated CASP1 then processes pro-IL-1β and pro-IL-18 and cleaves gasdermin D, with re-expression of CASP1 restoring N-GSDMD, IL-1β and IL-18 generation [#0, #7]. Inflammasome engagement is triggered by upstream danger inputs including manganese-induced lysosomal damage and cathepsin B release [#4] and intracellular chloride sensing through SGK1, which feeds an autocrine IL-1β amplification loop [#8]. CASP1 expression is set by epigenetic and transcriptional regulators: the histone methyltransferases G9A/EHMT2 and PRMT5 silence the gene via H3K9me2 and H4R3me2s respectively [#3, #7], while PRDM1 and IFNγ/STAT1 signaling directly activate its transcription [#9, #10]. Beyond canonical cytokine substrates, CASP1 cleaves the glucocorticoid receptor to reduce GR levels and confer glucocorticoid resistance [#2], and small metabolites such as kynurenine bind CASP1 directly to suppress its cleavage activity and dampen pyroptosis [#11]. CASP1 also acts non-catalytically as a scaffold: through its CARD domain it interacts with RPTOR/mTORC1 to constrain NF-κB signaling, and loss or CARD disruption triggers excessive NF-κB activity [#12]. Consistent with these dual roles, gain-of-function CASP1 variants drive both inflammasome hyperactivation and RIP2-dependent NF-κB activation in autoinflammatory disease, while other disease variants reveal scaffolding and subcellular-localization functions independent of catalysis [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the molecular identity of CASP1 as the protease responsible for converting inactive pro-IL-1β into active IL-1β, defining its founding biochemical function.\",\n      \"evidence\": \"Genomic cloning, transcription start site mapping, and FISH localization of the human gene\",\n      \"pmids\": [\"8034320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the enzyme is activated in cells\", \"No structural mechanism of substrate cleavage defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Distinguished CASP1's IL-1β-processing inflammatory role from a separate capacity to directly induce cell death in vivo, hinting at functions beyond cytokine maturation.\",\n      \"evidence\": \"Intradermal plasmid transfer in mouse skin with TUNEL staining and anti-IL-1β neutralization\",\n      \"pmids\": [\"10468192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway of the IL-1β-independent death was not defined\", \"Single-lab in vivo gain-of-function\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the glucocorticoid receptor as a non-canonical CASP1 substrate, explaining how inflammasome activation can drive glucocorticoid resistance.\",\n      \"evidence\": \"CASP1 overexpression/knockdown and inhibition in ALL cells with GR cleavage and transcriptional readouts\",\n      \"pmids\": [\"25938942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site on GR not mapped\", \"Generality beyond leukemia models untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed CASP1 expression is epigenetically repressed by G9A-mediated H3K9me2 and that this repression supports tumor invasion, placing CASP1 under chromatin-level control.\",\n      \"evidence\": \"shRNA knockdown, ChIP, luciferase promoter assay, and invasion/migration rescue in NSCLC\",\n      \"pmids\": [\"28383547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether de-repressed CASP1 acts catalytically or as scaffold here is unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected an environmental trigger to inflammasome activation by showing manganese activates NLRP3-CASP1 via lysosomal damage and cathepsin B release rather than autophagosome accumulation.\",\n      \"evidence\": \"In vivo Mn exposure plus BV2 microglia, CTSB inhibition, and CASP1 activity/cytokine assays\",\n      \"pmids\": [\"28318352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between CTSB and CASP1 activation step not biochemically resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that disease-associated CASP1 variants alter pyroptosome formation, nuclear localization, and cell mechanics, exposing scaffolding/localization roles independent of catalysis.\",\n      \"evidence\": \"Variant transduction in THP-1 monocytes with immunofluorescence, pyroptosome and deformability assays\",\n      \"pmids\": [\"31252176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking nuclear localization to function unknown\", \"Single-lab variant panel\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed a gain-of-function CASP1 variant simultaneously hyperactivates the inflammasome and RIP2-dependent NF-κB signaling, tying CASP1 to autoinflammatory disease through two pathways.\",\n      \"evidence\": \"Whole exome sequencing, patient PBMC caspase-1 activity and cytokine assays, NF-κB reporter assays\",\n      \"pmids\": [\"32556329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"Direct mechanism of RIP2 engagement by CASP1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended epigenetic control of CASP1 to PRMT5-mediated H4R3me2s and demonstrated that relieving this silencing promotes pyroptosis, linking CASP1 re-expression to gasdermin/cytokine output.\",\n      \"evidence\": \"PRMT5 knockdown/inhibition with CASP1 rescue and pyroptosis marker Western blots in myeloma, with in vivo validation\",\n      \"pmids\": [\"34531375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PRMT5 acts solely at the CASP1 promoter not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified intracellular chloride and SGK1 as upstream modulators of NLRP3-CASP1, defining an autocrine IL-1β amplification loop that reinforces inflammasome activity.\",\n      \"evidence\": \"Ionophore Cl- modulation in epithelial cells with VX-765, MCC950, SGK1 knockdown, and IL-1β/ROS measurements\",\n      \"pmids\": [\"33835494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chloride sensor for CASP1 not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided reciprocal co-IP evidence that CASP1 physically associates with NLRP3 and is activated upon ASC nucleation in a reconstituted system, anchoring CASP1 within the inflammasome complex.\",\n      \"evidence\": \"Co-IP in HEK293-iASC-NLRP3/CASP1 cells with inducible ASC, activity biosensor, and inhibitor panel\",\n      \"pmids\": [\"35221708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of the assembled complex not resolved\", \"Reconstituted overexpression system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CASP1 downstream of IFNγ/STAT1 signaling in ATRA-induced pyroptosis and differentiation of APL cells, defining a transcriptional activation route for CASP1.\",\n      \"evidence\": \"CASP1 overexpression and ATRA treatment in APL cells with pathway and pyroptosis/differentiation assays\",\n      \"pmids\": [\"36822457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT1 binding to CASP1 promoter not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated direct transcriptional activation of CASP1 by PRDM1 driving nucleus pulposus pyroptosis, completing a transcription-factor-level control node.\",\n      \"evidence\": \"mRNA-seq, ChIP, dual-luciferase reporter, and CASP1 knockdown epistasis with in vivo models\",\n      \"pmids\": [\"39432156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specificity of PRDM1-CASP1 regulation not explored\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed kynurenine directly binds CASP1 to inhibit its cleavage activity, identifying a metabolite-level brake on pyroptosis that shapes the tumor microenvironment.\",\n      \"evidence\": \"Surface plasmon resonance binding, CASP1 overexpression rescue, and VX-765 inhibition in M2 macrophages/RCC co-culture\",\n      \"pmids\": [\"41079603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on CASP1 not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a protease-independent scaffolding role for CASP1, where its CARD domain interacts with RPTOR/mTORC1 to restrain NF-κB and support leukemic growth.\",\n      \"evidence\": \"CASP1 deletion/CARD disruption, CASP1-RPTOR co-IP, NF-κB assays, and a pro-CASP1 PROTAC degrader with in vivo leukemia models\",\n      \"pmids\": [\"41500224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CASP1-RPTOR interaction unresolved\", \"How scaffolding suppresses NF-κB mechanistically not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CASP1's catalytic, pro-death, and scaffolding/RPTOR functions are partitioned and coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating CARD-scaffolding and protease states\", \"Switch between cytokine maturation, GR cleavage, and NF-κB control not defined\", \"Physiological substrate repertoire beyond IL-1β/IL-18/GSDMD/GR incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 7, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 13, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 6]}\n    ],\n    \"complexes\": [\"NLRP3 inflammasome\"],\n    \"partners\": [\"NLRP3\", \"ASC\", \"RPTOR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}