Affinage

CASP10

Caspase-10 · UniProt Q92851

Length
521 aa
Mass
59.0 kDa
Annotated
2026-06-09
42 papers in source corpus 4 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1996 High

    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

    PMID:8755496

    Open questions at the time
    • Effector-caspase activation shown in vitro, not within an intact cellular DISC
    • No structural model of the active enzyme
  2. 1996 Medium

    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

    PMID:8755496

    Open questions at the time
    • DED-FADD interaction inferred from sequence, not demonstrated by direct binding assay
    • Granzyme B maturation shown in vitro only
  3. 2002 Medium

    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

    PMID:12010812

    Open questions at the time
    • Single cell line and single method
    • Does not resolve how each domain contributes mechanistically
  4. 2019 Medium

    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

    PMID:31309545

    Open questions at the time
    • Epistatic ordering relative to CASP8 inferred from cleavage readouts, not direct enzymatic hierarchy
    • Single-lab patient cohort
  5. 2026 Medium

    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

    PMID:41703263

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CASP10 is physically recruited and activated at the FADD/death-receptor complex, and how its apoptotic and pyroptotic functions are partitioned, remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0016787 hydrolase activity 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 2
Partners
FADDGZMB

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Recombinant protein expression in E. coli, in vitro protease activity assay, peptide inhibitor assay, cleavage of recombinant substrates Proceedings of the National Academy of Sciences of the United States of America High 8755496
1996 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. Sequence analysis of cloned cDNA; in vitro cleavage assay with recombinant granzyme B Proceedings of the National Academy of Sciences of the United States of America Medium 8755496
2002 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. Mutational analysis of tumor-derived CASP10 variants expressed in 293 cells, apoptosis assay Blood Medium 12010812
2019 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. Flow cytometry apoptosis assay with FAS-ligand/TRAIL stimulation, western blot for CASP10, CASP8, and PARP cleavage in patient-derived cells British journal of haematology Medium 31309545
2026 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. CASP10 overexpression and knockdown in HUVECs, western blot for γH2AX, NLRP3, GSDMD-N, and IL-1β; cell death assays Journal of cellular and molecular medicine Medium 41703263

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proceedings of the National Academy of Sciences of the United States of America 672 8755496
2013 Assessment of protein disorder region predictions in CASP10. Proteins 128 23946100
2002 Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas. Blood 119 12010812
2014 Evaluation of predictions in the CASP10 model refinement category. Proteins 93 23900810
2013 Assessment of the assessment: evaluation of the model quality estimates in CASP10. Proteins 88 23780644
2013 Interplay of I-TASSER and QUARK for template-based and ab initio protein structure prediction in CASP10. Proteins 85 23760925
2014 Assessment of template-based protein structure predictions in CASP10. Proteins 81 24323734
2013 CASP prediction center infrastructure and evaluation measures in CASP10 and CASP ROLL. Proteins 78 24038551
2013 CASP10 results compared to those of previous CASP experiments. Proteins 72 24150928
2013 Assessment of template-free modeling in CASP10 and ROLL. Proteins 71 24343678
2013 Evaluation of residue-residue contact prediction in CASP10. Proteins 60 23760879
2013 Lessons from application of the UNRES force field to predictions of structures of CASP10 targets. Proceedings of the National Academy of Sciences of the United States of America 59 23980156
2005 Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant. Carcinogenesis 48 16251207
2014 Challenging the state of the art in protein structure prediction: Highlights of experimental target structures for the 10th Critical Assessment of Techniques for Protein Structure Prediction Experiment CASP10. Proteins 46 24318984
2013 i3Drefine software for protein 3D structure refinement and its assessment in CASP10. PloS one 40 23894517
2014 Assessment of ligand binding site predictions in CASP10. Proteins 38 24339001
2005 Variation in CASP10 gene is associated with idiopathic talipes equinovarus. Journal of pediatric orthopedics 36 16199938
2010 Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 31 20978178
2014 Designing and evaluating the MULTICOM protein local and global model quality prediction methods in the CASP10 experiment. BMC structural biology 30 24731387
2013 Protein structure modeling for CASP10 by multiple layers of global optimization. Proteins 30 23966235
2019 FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene. British journal of haematology 29 31309545
2015 Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation. Immunobiology 27 26323380
2013 Definition and classification of evaluation units for CASP10. Proteins 21 24123179
2012 Association between CASP8 and CASP10 polymorphisms and toxicity outcomes with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer. The oncologist 19 22843554
2020 Long noncoding RNA PVT1 facilitates high glucose-induced cardiomyocyte death through the miR-23a-3p/CASP10 axis. Cell biology international 16 33049089
2017 Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1, CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants. Pancreas 14 27984487
2013 Assessment of CASP10 contact-assisted predictions. Proteins 14 23873510
2010 Mutational analysis of CASP10 gene in colon, breast, lung and hepatocellular carcinomas. Pathology 14 20025484
2016 Atypical presentation of autoimmune lymphoproliferative syndrome due to CASP10 mutation. Immunology letters 13 27378136
2021 Relationship Between CASP9 and CASP10 Gene Polymorphisms and Cancer Susceptibility: Evidence from an Updated Meta-analysis. Applied biochemistry and biotechnology 12 34463927
2012 Protein structure prediction: challenging targets for CASP10. Journal of biomolecular structure & dynamics 12 22731875
2009 Mutational analysis of CASP10 gene in acute leukaemias and multiple myelomas. Pathology 9 19900088
2012 Role of CASP-10 gene polymorphisms in cancer susceptibility: a HuGE review and meta-analysis. Genetics and molecular research : GMR 8 23212337
2011 Exonic deletion of CASP10 in a patient presenting with systemic juvenile idiopathic arthritis, but not with autoimmune lymphoproliferative syndrome type IIa. International journal of immunogenetics 7 21382177
2021 Variants in CASP10, a diagnostic challenge: Single center experience and review of the literature. Clinical immunology (Orlando, Fla.) 6 34329798
2013 Association of CASP9, CASP10 gene polymorphisms and tea drinking with colorectal cancer risk in the Han Chinese population. Journal of Zhejiang University. Science. B 6 23303631
2008 Association of polymorphisms in CASP10 and CASP8 with FEV(1)/FVC and bronchial hyperresponsiveness in ethnically diverse asthmatics. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 6 18823309
2023 Gelsolin Inhibits the Proliferation of Colon Cancer Cells by Enhancing the Expression of TNFR2/CASP10 as a Death Receptor Pathway. Protein and peptide letters 5 36734906
2015 CASP10-BCL::Fold efficiently samples topologies of large proteins. Proteins 5 25581562
2025 Comprehensive Pan-cancer Analysis Revealed CASP10 As a Promising Biomarker For Diverse Tumor Types. International journal of immunopathology and pharmacology 3 40152300
2026 Systematic Identification and Functional Validation of CASP10 as a DNA-Damage-Responsive Driver of Endothelial Pyroptosis in Atherosclerosis. Journal of cellular and molecular medicine 0 41703263
2025 Monomeric class II chelatase with four histidine residues at the active site, designated Mch4 chelatase, shows evolutionary trails from ancestral to descendant-types. Journal of inorganic biochemistry 0 40706352

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