{"gene":"CASP10","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1996,"finding":"CASP10 (Mch4) encodes an active aspartate-specific cysteine protease with a QACQG pentapeptide active site (instead of the typical QACRG), which is potently inhibited by DEVD-CHO (Ki = 14 nM). The mature protease cleaves recombinant proCPP32 (pro-caspase-3) and proMch3 (pro-caspase-3/7) at a conserved IXXD-S sequence to produce large and small subunits of the active downstream caspases, establishing CASP10 as an upstream initiator caspase that activates effector caspases.","method":"Recombinant protein expression in E. coli, in vitro protease activity assay, peptide inhibitor assay, cleavage of recombinant substrates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution of enzymatic activity, active-site characterization, substrate cleavage assay with defined cleavage sites, inhibition kinetics","pmids":["8755496"],"is_preprint":false},{"year":1996,"finding":"CASP10 (Mch4) contains two N-terminal FADD-like death effector domains (DEDs), suggesting it can interact with FADD and participate in the Fas/death receptor apoptotic pathway. Granzyme B also cleaves proMch4 at a homologous IXXD-A processing sequence to generate mature CASP10, placing it downstream of granzyme B in the cytotoxic lymphocyte apoptotic pathway.","method":"Sequence analysis of cloned cDNA; in vitro cleavage assay with recombinant granzyme B","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain identification from sequence plus in vitro cleavage validation; DED-FADD interaction inferred structurally but not directly demonstrated by binding experiment in this abstract","pmids":["8755496"],"is_preprint":false},{"year":2002,"finding":"Tumor-derived inactivating somatic mutations in CASP10 (including mutations in the prodomain, p17 large protease subunit, and p12 small protease subunit) suppress apoptosis when expressed in 293 cells, demonstrating that the pro-apoptotic function of CASP10 requires intact catalytic and structural domains.","method":"Mutational analysis of tumor-derived CASP10 variants expressed in 293 cells, apoptosis assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function expression in cells with defined apoptosis phenotype; single lab, single method","pmids":["12010812"],"is_preprint":false},{"year":2019,"finding":"CASP10 variants (I406L, V410I, Y446C) impair FAS-ligand/TRAIL-induced apoptosis in patient lymphocytes, with functional studies showing reduced CASP10, CASP8, and PARP cleavage activity, placing CASP10 in the FAS-mediated extrinsic apoptosis pathway upstream of CASP8 and PARP.","method":"Flow cytometry apoptosis assay with FAS-ligand/TRAIL stimulation, western blot for CASP10, CASP8, and PARP cleavage in patient-derived cells","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional apoptosis assay in patient-derived cells with protein-level readout; single lab, multiple methods","pmids":["31309545"],"is_preprint":false},{"year":2026,"finding":"CASP10 is necessary and sufficient for ox-LDL-induced DNA damage and pyroptosis in human umbilical vein endothelial cells (HUVECs): CASP10 overexpression increased γH2AX accumulation, NLRP3 expression, GSDMD-N cleavage, and IL-1β release, while CASP10 knockdown attenuated all these effects, identifying a role for CASP10 in linking DNA damage signaling to the NLRP3/GSDMD pyroptotic pathway in endothelial cells.","method":"CASP10 overexpression and knockdown in HUVECs, western blot for γH2AX, NLRP3, GSDMD-N, and IL-1β; cell death assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple mechanistic readouts in a defined cell system; single lab, not yet replicated","pmids":["41703263"],"is_preprint":false}],"current_model":"CASP10 (Mch4/FLICE-2) is an initiator cysteine protease with a QACQG active site and two N-terminal death effector domains (DEDs) that allow recruitment to the FADD/death receptor signaling complex; upon activation (including by granzyme B cleavage), it proteolytically processes downstream effector caspases (caspase-3/CPP32, caspase-7/Mch3) at IXXD-S sequences to drive apoptosis, and inactivating somatic or germline mutations that disrupt its prodomain or catalytic subunits block FAS-mediated and intrinsic apoptosis; more recently, CASP10 has also been shown to link ox-LDL-induced DNA damage to endothelial pyroptosis via NLRP3/GSDMD activation."},"narrative":{"mechanistic_narrative":"CASP10 (Mch4/FLICE-2) is an initiator cysteine protease that activates the apoptotic caspase cascade downstream of death receptors and cytotoxic lymphocytes [PMID:8755496]. It is an aspartate-specific protease carrying an atypical QACQG active-site pentapeptide and is potently inhibited by DEVD-CHO; the mature enzyme cleaves pro-caspase-3 (CPP32) and pro-caspase-3/7 (Mch3) at conserved IXXD-S sequences to generate the active large and small subunits of these effector caspases, establishing CASP10 as an upstream initiator caspase [PMID:8755496]. Its two N-terminal death effector domains link it to FADD/death-receptor signaling, and it is also matured by granzyme B cleavage at a homologous IXXD-A site, positioning it in the cytotoxic lymphocyte apoptotic pathway [PMID:8755496]. The pro-apoptotic function depends on intact prodomain and catalytic (p17/p12) subunits: tumor-derived and germline variants disrupting these regions suppress apoptosis and impair FAS-ligand/TRAIL-induced cleavage of CASP10, CASP8, and PARP in cells [PMID:12010812, PMID:31309545]. Beyond apoptosis, CASP10 is necessary and sufficient for ox-LDL-induced DNA damage and pyroptosis in endothelial cells, driving γH2AX accumulation, NLRP3 expression, GSDMD-N cleavage, and IL-1β release [PMID:41703263].","teleology":[{"year":1996,"claim":"Established CASP10 as an enzymatically active initiator caspase by defining its active site and demonstrating it cleaves and activates downstream effector caspases.","evidence":"Recombinant expression in E. coli with in vitro protease, inhibitor kinetics, and substrate cleavage assays on pro-caspase-3 and pro-caspase-3/7","pmids":["8755496"],"confidence":"High","gaps":["Effector-caspase activation shown in vitro, not within an intact cellular DISC","No structural model of the active enzyme"]},{"year":1996,"claim":"Placed CASP10 in death-receptor and granzyme B apoptotic pathways by identifying its N-terminal DEDs and demonstrating granzyme B maturation.","evidence":"cDNA sequence analysis identifying tandem DEDs; in vitro cleavage by recombinant granzyme B","pmids":["8755496"],"confidence":"Medium","gaps":["DED-FADD interaction inferred from sequence, not demonstrated by direct binding assay","Granzyme B maturation shown in vitro only"]},{"year":2002,"claim":"Showed that the pro-apoptotic activity of CASP10 requires intact catalytic and structural domains, since tumor-derived mutations across prodomain, p17, and p12 are loss-of-function.","evidence":"Expression of tumor-derived CASP10 variants in 293 cells with apoptosis readout","pmids":["12010812"],"confidence":"Medium","gaps":["Single cell line and single method","Does not resolve how each domain contributes mechanistically"]},{"year":2019,"claim":"Confirmed CASP10's role in FAS-mediated extrinsic apoptosis upstream of CASP8 and PARP through functional analysis of patient variants.","evidence":"FAS-ligand/TRAIL apoptosis assays and western blot for CASP10, CASP8, and PARP cleavage in patient-derived lymphocytes","pmids":["31309545"],"confidence":"Medium","gaps":["Epistatic ordering relative to CASP8 inferred from cleavage readouts, not direct enzymatic hierarchy","Single-lab patient cohort"]},{"year":2026,"claim":"Extended CASP10 function beyond apoptosis to a pyroptotic axis linking DNA damage to NLRP3/GSDMD activation in endothelial cells.","evidence":"CASP10 overexpression and knockdown in HUVECs with western blot for γH2AX, NLRP3, GSDMD-N, IL-1β and cell death assays","pmids":["41703263"],"confidence":"Medium","gaps":["Single lab, not yet independently replicated","Mechanism connecting CASP10 to DNA damage signaling and NLRP3 activation unresolved","Whether CASP10 catalytic activity is required for this axis not established"]},{"year":null,"claim":"How CASP10 is physically recruited and activated at the FADD/death-receptor complex, and how its apoptotic and pyroptotic functions are partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct biochemical demonstration of DED-FADD binding in the corpus","No structural data on the activated complex","Relationship between CASP10's apoptotic and NLRP3/GSDMD pyroptotic roles uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["FADD","GZMB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92851","full_name":"Caspase-10","aliases":["Apoptotic protease Mch-4","FAS-associated death domain protein interleukin-1B-converting enzyme 2","FLICE2","ICE-like apoptotic protease 4"],"length_aa":521,"mass_kda":59.0,"function":"Involved in the activation cascade of caspases responsible for apoptosis execution. Recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. May participate in the granzyme B apoptotic pathways. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP8 and CASP9. Hydrolyzes the small- molecule substrates, Tyr-Val-Ala-Asp-|-AMC and Asp-Glu-Val-Asp-|-AMC Isoform 7 can enhance NF-kappaB activity but promotes only slight apoptosis Isoform C is proteolytically inactive","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q92851/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASP10","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CASP10","total_profiled":1310},"omim":[{"mim_id":"617388","title":"AUTOINFLAMMATION WITH ARTHRITIS AND DYSKERATOSIS; AIADK","url":"https://www.omim.org/entry/617388"},{"mim_id":"617078","title":"DEATH EFFECTOR DOMAIN-CONTAINING PROTEIN 2; DEDD2","url":"https://www.omim.org/entry/617078"},{"mim_id":"613659","title":"GASTRIC CANCER","url":"https://www.omim.org/entry/613659"},{"mim_id":"612313","title":"GLASS SYNDROME; GLASS","url":"https://www.omim.org/entry/612313"},{"mim_id":"606841","title":"DEATH EFFECTOR DOMAIN-CONTAINING PROTEIN; DEDD","url":"https://www.omim.org/entry/606841"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CASP10"},"hgnc":{"alias_symbol":["MCH4","FLICE-2"],"prev_symbol":[]},"alphafold":{"accession":"Q92851","domains":[{"cath_id":"1.10.533.10","chopping":"21-112","consensus_level":"high","plddt":93.5873,"start":21,"end":112},{"cath_id":"1.10.533.10","chopping":"118-197","consensus_level":"high","plddt":88.6673,"start":118,"end":197},{"cath_id":"3.40.50.1460","chopping":"283-410_432-504","consensus_level":"high","plddt":75.3592,"start":283,"end":504}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92851","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92851-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92851-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASP10","jax_strain_url":"https://www.jax.org/strain/search?query=CASP10"},"sequence":{"accession":"Q92851","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92851.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92851/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92851"}},"corpus_meta":[{"pmid":"8755496","id":"PMC_8755496","title":"In 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The mature protease cleaves recombinant proCPP32 (pro-caspase-3) and proMch3 (pro-caspase-3/7) at a conserved IXXD-S sequence to produce large and small subunits of the active downstream caspases, establishing CASP10 as an upstream initiator caspase that activates effector caspases.\",\n      \"method\": \"Recombinant protein expression in E. coli, in vitro protease activity assay, peptide inhibitor assay, cleavage of recombinant substrates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution of enzymatic activity, active-site characterization, substrate cleavage assay with defined cleavage sites, inhibition kinetics\",\n      \"pmids\": [\"8755496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CASP10 (Mch4) contains two N-terminal FADD-like death effector domains (DEDs), suggesting it can interact with FADD and participate in the Fas/death receptor apoptotic pathway. Granzyme B also cleaves proMch4 at a homologous IXXD-A processing sequence to generate mature CASP10, placing it downstream of granzyme B in the cytotoxic lymphocyte apoptotic pathway.\",\n      \"method\": \"Sequence analysis of cloned cDNA; in vitro cleavage assay with recombinant granzyme B\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain identification from sequence plus in vitro cleavage validation; DED-FADD interaction inferred structurally but not directly demonstrated by binding experiment in this abstract\",\n      \"pmids\": [\"8755496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tumor-derived inactivating somatic mutations in CASP10 (including mutations in the prodomain, p17 large protease subunit, and p12 small protease subunit) suppress apoptosis when expressed in 293 cells, demonstrating that the pro-apoptotic function of CASP10 requires intact catalytic and structural domains.\",\n      \"method\": \"Mutational analysis of tumor-derived CASP10 variants expressed in 293 cells, apoptosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function expression in cells with defined apoptosis phenotype; single lab, single method\",\n      \"pmids\": [\"12010812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CASP10 variants (I406L, V410I, Y446C) impair FAS-ligand/TRAIL-induced apoptosis in patient lymphocytes, with functional studies showing reduced CASP10, CASP8, and PARP cleavage activity, placing CASP10 in the FAS-mediated extrinsic apoptosis pathway upstream of CASP8 and PARP.\",\n      \"method\": \"Flow cytometry apoptosis assay with FAS-ligand/TRAIL stimulation, western blot for CASP10, CASP8, and PARP cleavage in patient-derived cells\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional apoptosis assay in patient-derived cells with protein-level readout; single lab, multiple methods\",\n      \"pmids\": [\"31309545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CASP10 is necessary and sufficient for ox-LDL-induced DNA damage and pyroptosis in human umbilical vein endothelial cells (HUVECs): CASP10 overexpression increased γH2AX accumulation, NLRP3 expression, GSDMD-N cleavage, and IL-1β release, while CASP10 knockdown attenuated all these effects, identifying a role for CASP10 in linking DNA damage signaling to the NLRP3/GSDMD pyroptotic pathway in endothelial cells.\",\n      \"method\": \"CASP10 overexpression and knockdown in HUVECs, western blot for γH2AX, NLRP3, GSDMD-N, and IL-1β; cell death assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple mechanistic readouts in a defined cell system; single lab, not yet replicated\",\n      \"pmids\": [\"41703263\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASP10 (Mch4/FLICE-2) is an initiator cysteine protease with a QACQG active site and two N-terminal death effector domains (DEDs) that allow recruitment to the FADD/death receptor signaling complex; upon activation (including by granzyme B cleavage), it proteolytically processes downstream effector caspases (caspase-3/CPP32, caspase-7/Mch3) at IXXD-S sequences to drive apoptosis, and inactivating somatic or germline mutations that disrupt its prodomain or catalytic subunits block FAS-mediated and intrinsic apoptosis; more recently, CASP10 has also been shown to link ox-LDL-induced DNA damage to endothelial pyroptosis via NLRP3/GSDMD activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CASP10 (Mch4/FLICE-2) is an initiator cysteine protease that activates the apoptotic caspase cascade downstream of death receptors and cytotoxic lymphocytes [#0, #1]. It is an aspartate-specific protease carrying an atypical QACQG active-site pentapeptide and is potently inhibited by DEVD-CHO; the mature enzyme cleaves pro-caspase-3 (CPP32) and pro-caspase-3/7 (Mch3) at conserved IXXD-S sequences to generate the active large and small subunits of these effector caspases, establishing CASP10 as an upstream initiator caspase [#0]. Its two N-terminal death effector domains link it to FADD/death-receptor signaling, and it is also matured by granzyme B cleavage at a homologous IXXD-A site, positioning it in the cytotoxic lymphocyte apoptotic pathway [#1]. The pro-apoptotic function depends on intact prodomain and catalytic (p17/p12) subunits: tumor-derived and germline variants disrupting these regions suppress apoptosis and impair FAS-ligand/TRAIL-induced cleavage of CASP10, CASP8, and PARP in cells [#2, #3]. Beyond apoptosis, CASP10 is necessary and sufficient for ox-LDL-induced DNA damage and pyroptosis in endothelial cells, driving γH2AX accumulation, NLRP3 expression, GSDMD-N cleavage, and IL-1β release [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established CASP10 as an enzymatically active initiator caspase by defining its active site and demonstrating it cleaves and activates downstream effector caspases.\",\n      \"evidence\": \"Recombinant expression in E. coli with in vitro protease, inhibitor kinetics, and substrate cleavage assays on pro-caspase-3 and pro-caspase-3/7\",\n      \"pmids\": [\"8755496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Effector-caspase activation shown in vitro, not within an intact cellular DISC\",\n        \"No structural model of the active enzyme\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Placed CASP10 in death-receptor and granzyme B apoptotic pathways by identifying its N-terminal DEDs and demonstrating granzyme B maturation.\",\n      \"evidence\": \"cDNA sequence analysis identifying tandem DEDs; in vitro cleavage by recombinant granzyme B\",\n      \"pmids\": [\"8755496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DED-FADD interaction inferred from sequence, not demonstrated by direct binding assay\",\n        \"Granzyme B maturation shown in vitro only\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that the pro-apoptotic activity of CASP10 requires intact catalytic and structural domains, since tumor-derived mutations across prodomain, p17, and p12 are loss-of-function.\",\n      \"evidence\": \"Expression of tumor-derived CASP10 variants in 293 cells with apoptosis readout\",\n      \"pmids\": [\"12010812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell line and single method\",\n        \"Does not resolve how each domain contributes mechanistically\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed CASP10's role in FAS-mediated extrinsic apoptosis upstream of CASP8 and PARP through functional analysis of patient variants.\",\n      \"evidence\": \"FAS-ligand/TRAIL apoptosis assays and western blot for CASP10, CASP8, and PARP cleavage in patient-derived lymphocytes\",\n      \"pmids\": [\"31309545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Epistatic ordering relative to CASP8 inferred from cleavage readouts, not direct enzymatic hierarchy\",\n        \"Single-lab patient cohort\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended CASP10 function beyond apoptosis to a pyroptotic axis linking DNA damage to NLRP3/GSDMD activation in endothelial cells.\",\n      \"evidence\": \"CASP10 overexpression and knockdown in HUVECs with western blot for γH2AX, NLRP3, GSDMD-N, IL-1β and cell death assays\",\n      \"pmids\": [\"41703263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, not yet independently replicated\",\n        \"Mechanism connecting CASP10 to DNA damage signaling and NLRP3 activation unresolved\",\n        \"Whether CASP10 catalytic activity is required for this axis not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CASP10 is physically recruited and activated at the FADD/death-receptor complex, and how its apoptotic and pyroptotic functions are partitioned, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical demonstration of DED-FADD binding in the corpus\",\n        \"No structural data on the activated complex\",\n        \"Relationship between CASP10's apoptotic and NLRP3/GSDMD pyroptotic roles uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FADD\", \"GZMB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}