Affinage

CASP4

Caspase-4 · UniProt P49662

Length
377 aa
Mass
43.3 kDa
Annotated
2026-06-09
100 papers in source corpus 2 papers cited in narrative 2 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASP4 (ICH-2/TX) is a catalytically active cysteine protease of the ICE family that participates in apoptotic proteolysis when expressed intracellularly (PMID:7797510, PMID:7642516). Purified recombinant CASP4 cleaves peptide substrates in cell-free assays, and its inhibitor profile and substrate preference overlap with but are distinct from those of ICE, indicating that CASP4 has its own in vivo substrate specificity (PMID:7797510). Within cells, CASP4 cleaves poly(ADP-ribose) polymerase (PARP) in a pattern identical to that observed in apoptotic cells, and its overexpression is sufficient to induce apoptosis (PMID:7797510, PMID:7642516). Beyond this in vitro and overexpression-based characterization of its protease activity and PARP cleavage, no further mechanistic detail — including physiological activating signals, upstream regulators, or endogenous complex membership — has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 1995 High

    Establishing whether CASP4 is itself an enzyme answered the basic question of its biochemical identity, showing it is a bona fide ICE-family cysteine protease rather than a passive family member.

    Evidence In vitro protease assay with purified recombinant ICH-2, inhibitor profiling, and overexpression-induced apoptosis in insect cells

    PMID:7797510

    Open questions at the time
    • No endogenous substrate identified in this study
    • Inhibitor/substrate overlap with ICE leaves the distinct in vivo specificity undefined
    • Physiological activating signal and upstream protease not addressed
  2. 1995 High

    Identifying a cellular substrate addressed what CASP4 actually does in cells, demonstrating it cleaves PARP in the apoptotic pattern and thereby linking it to programmed cell death proteolysis.

    Evidence COS cell co-transfection of TX with PARP, with in vitro confirmation using purified recombinant enzyme on PARP substrate

    PMID:7642516

    Open questions at the time
    • PARP cleavage shown under co-expression, not at endogenous CASP4 levels
    • Whether PARP is a direct physiological substrate versus an overexpression artifact is unresolved
    • No identification of the apoptotic pathway context or activating caspase upstream of CASP4

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous activation mechanism, physiological substrates, and complex membership of CASP4 remain undefined in the available corpus.
  • No upstream activating signal or platform identified
  • No endogenous substrate confirmed beyond overexpression-based PARP cleavage
  • No structural model or subcellular localization data

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 2

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ICH-2 (CASP4) is a functional cysteine protease in vitro: purified recombinant ICH-2 cleaved substrates in a cell-free protease assay. Its inhibitor profile and substrate cleavage pattern overlapped with but differed from ICE, suggesting distinct in vivo substrate specificities. In vitro protease assay with purified recombinant protein; inhibitor profiling; overexpression in insect cells inducing apoptosis The Journal of biological chemistry High 7797510
1995 TX (CASP4), when co-expressed with PARP in COS cells, cleaved poly(ADP-ribose) polymerase (PARP) in a pattern identical to that seen in apoptotic cells, demonstrating PARP is a substrate of CASP4 inside the cell. ICE itself also cleaved PARP in vitro but required 50–100-fold higher concentration than for IL-1β precursor processing. COS cell co-transfection assay (PARP + TX/ICE/Nedd-2); in vitro cleavage assay with purified recombinant ICE on PARP substrate The Journal of biological chemistry High 7642516

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nature genetics 656 7951320
2016 The All E. coli TX-TL Toolbox 2.0: A Platform for Cell-Free Synthetic Biology. ACS synthetic biology 332 26818434
2002 PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). The American journal of surgical pathology 271 12459622
2013 Protocols for implementing an Escherichia coli based TX-TL cell-free expression system for synthetic biology. Journal of visualized experiments : JoVE 270 24084388
1995 Identification and characterization of ICH-2, a novel member of the interleukin-1 beta-converting enzyme family of cysteine proteases. The Journal of biological chemistry 265 7797510
1996 The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Human molecular genetics 225 8872474
2003 A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 215 12917640
1997 Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 207 9010221
2013 Linear DNA for rapid prototyping of synthetic biological circuits in an Escherichia coli based TX-TL cell-free system. ACS synthetic biology 203 24303785
2020 Biodegradable and Electroactive Regenerated Bacterial Cellulose/MXene (Ti3 C2 Tx ) Composite Hydrogel as Wound Dressing for Accelerating Skin Wound Healing under Electrical Stimulation. Advanced healthcare materials 198 32864898
1996 Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 178 8986805
2002 Monophasic fibrous and poorly differentiated synovial sarcoma: immunohistochemical reassessment of 60 t(X;18)(SYT-SSX)-positive cases. The American journal of surgical pathology 167 12409719
1995 Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2. The Journal of biological chemistry 161 7642516
1994 Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family. Genes, chromosomes & cancer 155 7529552
2008 DIALIGN-TX: greedy and progressive approaches for segment-based multiple sequence alignment. Algorithms for molecular biology : AMB 136 18505568
1997 The SYT protein involved in the t(X;18) synovial sarcoma translocation is a transcriptional activator localised in nuclear bodies. Human molecular genetics 125 9285794
2014 Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems. ACS synthetic biology 121 24621257
1976 Intrachromosomal gene mapping in man: assignment of nucleoside phosphorylase to region 14cen leads to 14q21 by interspecific hybridization of cells with a t(X;14) (p22;q21) translocation. Somatic cell genetics 105 829289
2010 TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases. European journal of cancer (Oxford, England : 1990) 83 20189377
2007 Mitochondrial structure and function in the untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease. Molecular genetics and metabolism 77 17981064
2001 Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase. Human molecular genetics 74 11157799
1996 Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations. Blood 70 8634440
2021 Ultrathin 2D Titanium Carbide MXene (Ti3 C2 Tx ) Nanoflakes Activate WNT/HIF-1α-Mediated Metabolism Reprogramming for Periodontal Regeneration. Advanced healthcare materials 66 34586717
2017 Streptomyces venezuelae TX-TL - a next generation cell-free synthetic biology tool. Biotechnology journal 65 28139884
1980 Primary and secondary nonrandom X chromosome inactivation in early female mouse embryos carrying Searle's translocation T(X; 16)16H. Chromosoma 64 7449570
2001 Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer research 63 11358836
2001 Impairment of MAD2B-PRCC interaction in mitotic checkpoint defective t(X;1)-positive renal cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 63 11717438
2023 Small-size Ti3C2Tx MXene nanosheets coated with metal-polyphenol nanodots for enhanced cancer photothermal therapy and anti-inflammation. Acta biomaterialia 62 36708854
1995 Mapping the X chromosome breakpoint in two papillary renal cell carcinoma cell lines with a t(X;1)(p11.2;q21.2) and the first report of a female case. Cytogenetics and cell genetics 56 7587394
2002 SYT-SSX is critical for cyclin D1 expression in synovial sarcoma cells: a gain of function of the t(X;18)(p11.2;q11.2) translocation. Cancer research 53 12097301
2022 Ti3 C2 Tx MXene Composite 3D Hydrogel Potentiates mTOR Signaling to Promote the Generation of Functional Hair Cells in Cochlea Organoids. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 51 36117048
2002 MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site. Oncogene 47 12096348
2012 t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth. Blood 45 22966169
2002 TX-1123: an antitumor 2-hydroxyarylidene-4-cyclopentene-1,3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity. Bioorganic & medicinal chemistry 45 12150871
2006 Expression of the water-channel protein aquaporin 4 in the H-Tx rat: possible compensatory role in spontaneously arrested hydrocephalus. Journal of neurosurgery 42 17184078
2006 Modified ELISPOT technique--highly significant inverse correlation of post-Tx donor-reactive IFNgamma-producing cell frequencies with 6 and 12 months graft function in kidney transplant recipients. Transplant immunology 39 17138059
1993 Identification of a yeast artificial chromosome (YAC) spanning the synovial sarcoma-specific t(X;18)(p11.2;q11.2) breakpoint. Genes, chromosomes & cancer 39 7682104
1991 Thromboxane (Tx) A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti-aggregatory efficacy in human platelets. British journal of pharmacology 38 1826620
1984 Behavioral testing of progenies of Tx (hypothyroid) and growth hormone-treated Tx rats: an animal model for mental retardation. Neuroendocrinology 38 6539858
1994 The MTCP-1/c6.1B gene encodes for a cytoplasmic 8 kD protein overexpressed in T cell leukemia bearing a t(X;14) translocation. Oncogene 36 7970717
2011 t(X;14)(p11.4;q32.33) is recurrent in marginal zone lymphoma and up-regulates GPR34. Haematologica 35 22058210
2002 The SYT-SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin A and D1. A link between t(X;18)(p11.2; q11.2) and the cell cycle machinery. Oncogene 34 12173050
2011 The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4. International journal of cancer 33 20340132
2012 Biochemical, pharmacological, and structural characterization of new basic PLA2 Bbil-TX from Bothriopsis bilineata snake venom. BioMed research international 32 23509754
2004 PRDX4, a member of the peroxiredoxin family, is fused to AML1 (RUNX1) in an acute myeloid leukemia patient with a t(X;21)(p22;q22). Genes, chromosomes & cancer 32 15188461
2021 Muscle Fatigue Sensor Based on Ti3 C2 Tx MXene Hydrogel. Small methods 30 34928032
2004 Antiplatelet activity of J78 (2-Chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an antithrombotic agent, is mediated by thromboxane (TX) A2 receptor blockade with TXA2 synthase inhibition and suppression of cytosolic Ca2+ mobilization. The Journal of pharmacology and experimental therapeutics 30 15328379
2022 Accessory Genomes Drive Independent Spread of Carbapenem-Resistant Klebsiella pneumoniae Clonal Groups 258 and 307 in Houston, TX. mBio 29 35357213
2005 Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes. Genes, chromosomes & cancer 29 15543602
2023 Biocompatible and Oxidation-Resistant Ti3 C2 Tx MXene with Halogen-Free Surface Terminations. Small methods 28 36929585
2016 Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016. Human genomics 28 27294413
2018 Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M. Circulation research 27 29298774
2008 The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus. British journal of haematology 27 19055661
2006 The SYT-SSX fusion protein down-regulates the cell proliferation regulator COM1 in t(x;18) synovial sarcoma. Molecular and cellular biology 27 17101797
2001 New antimetastatic hypoxic cell radiosensitizers: design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues. Bioorganic & medicinal chemistry 27 11249137
2021 Impact of a School-Based Gardening, Cooking, Nutrition Intervention on Diet Intake and Quality: The TX Sprouts Randomized Controlled Trial. Nutrients 26 34578959
2000 The expression of inherited hydrocephalus in H-Tx rats. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 26 11048632
2000 Effect of DT-TX 30, a combined thromboxane synthase inhibitor and thromboxane receptor antagonist, on retinal vascularity in experimental diabetes mellitus. Thrombosis research 25 10680643
2001 Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat. Mammalian genome : official journal of the International Mammalian Genome Society 24 11178739
2023 Ti3C2Tx MXene -facilitated non-selective trapping effect: Efficient SERS detection of exosomal PD-L1. Biosensors & bioelectronics 23 37364303
2020 Gandouling Tablets Inhibit Excessive Mitophagy in Toxic Milk (TX) Model Mouse of Wilson Disease via Pink1/Parkin Pathway. Evidence-based complementary and alternative medicine : eCAM 23 33456485
2008 Copper Induces Apoptosis of Neuroblastoma Cells Via Post-translational Regulation of the Expression of Bcl-2-family Proteins and the tx Mouse is a Better Model of Hepatic than Brain Cu Toxicity. International journal of clinical and experimental medicine 23 19079689
2004 Functional disomy of Xp including duplication of DAX1 gene with sex reversal due to t(X;Y)(p21.2;p11.3). American journal of medical genetics. Part A 23 15216557
2002 Abnormal expression of the KLF8 (ZNF741) gene in a female patient with an X;autosome translocation t(X;21)(p11.2;q22.3) and non-syndromic mental retardation. Journal of medical genetics 23 11836360
2001 Chromosomal linkage associated with disease severity in the hydrocephalic H-Tx rat. Behavior genetics 23 11529267
2018 Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease. Human molecular genetics 22 30010856
2013 Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. British journal of pharmacology 22 23647513
2005 ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22). Leukemia research 22 16303180
2008 Inactivation of the CDKL3 gene at 5q31.1 by a balanced t(X;5) translocation associated with nonspecific mild mental retardation. American journal of medical genetics. Part A 21 18412109
2004 Relationship between plasma Cystatin C and creatinine in chronic renal diseases and Tx-transplant patients. Clinical biochemistry 21 14725938
2023 Impact of the V410L kdr mutation and co-occurring genotypes at kdr sites 1016 and 1534 in the VGSC on the probability of survival of the mosquito Aedes aegypti (L.) to Permanone in Harris County, TX, USA. PLoS neglected tropical diseases 20 36689414
2019 Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI-ceruloplasmin expression in liver macrophages. Metallomics : integrated biometal science 20 31011744
2006 Minimal phenotype in a girl with trisomy 15q due to t(X;15)(q22.3;q11.2) translocation. American journal of medical genetics. Part A 20 16470732
2004 Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers. Bioorganic & medicinal chemistry 20 15336271
1993 A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation. The Biochemical journal 20 8257436
2023 Nanoenzyme-Reinforced Multifunctional Scaffold Based on Ti3C2Tx MXene Nanosheets for Promoting Structure-Functional Skeletal Muscle Regeneration via Electroactivity and Microenvironment Management. Nano letters 19 37578316
2013 Cell cycle arrest and apoptosis induced by 1α,25(OH)2D3 and TX 527 in Kaposi sarcoma is VDR dependent. The Journal of steroid biochemistry and molecular biology 19 24316429
2000 Hydrocephalus in the H-Tx rat: a monogenic disease? Experimental neurology 19 10785451
2003 Antiangiogenic hypoxic cytotoxin TX-402 inhibits hypoxia-inducible factor 1 signaling pathway. Anticancer research 18 14666730
2023 Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering. Advanced healthcare materials 16 37341969
2022 Ti3C2Tx MXene nanosheets enhance the tolerance of Torreya grandis to Pb stress. Journal of hazardous materials 16 37056011
2021 Tuning Cell-Free Composition Controls the Time Delay, Dynamics, and Productivity of TX-TL Expression. ACS synthetic biology 16 34498860
2004 Analysis of TGF-beta2 and TGF-beta3 expression in the hydrocephalic H-Tx rat brain. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 16 15375625
1994 DNA rearrangements and altered transcripts of the MLL gene in a human T-ALL cell line Karpas 45 with a t(X;11) (q13;q23) translocation. Genes, chromosomes & cancer 16 7515665
1993 Association of HSP72 with the nuclear (TX-100-insoluble) fraction upon heating tolerant and non-tolerant HeLa S3 cells. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 16 8433029
2008 Analysis of neuronal cell death in the cerebral cortex of H-Tx rats with compensated hydrocephalus. Journal of neurosurgery. Pediatrics 15 18352806
2001 Fate of the biological control agent Pseudomonas aureofaciens TX-1 after application to turfgrass. Applied and environmental microbiology 15 11472930
2023 T-Cell Prolymphocytic Leukemia With t(X;14)(q28;q11.2): A Clinicopathologic Study of 15 Cases. American journal of clinical pathology 14 36883805
2023 Ti3 C2 TX MXene Ink Direct Writing Flexible Sensors for Disposable Paper Toys. Small (Weinheim an der Bergstrasse, Germany) 14 37162447
2019 In vitro studies revealed a downregulation of Wnt/β-catenin cascade by active vitamin D and TX 527 analog in a Kaposi's sarcoma cellular model. Toxicology in vitro : an international journal published in association with BIBRA 14 31838186
2011 Spread of X-chromosome inactivation into chromosome 15 is associated with Prader-Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation. Human genetics 14 21735174
2006 Heterotaxy and cardiac defect in a girl with chromosome translocation t(X;1)(q26;p13.1) and involvement of ZIC3. European journal of human genetics : EJHG 14 16926859
2023 The performance of whole genome bisulfite sequencing on DNBSEQ-Tx platform examined by different library preparation strategies. Heliyon 13 37292292
2021 A sensitive electrochemical DNA sensor for detecting Helicobacter pylori based on accordion-like Ti3C2Tx: a simple strategy. Analytical and bioanalytical chemistry 13 34013401
2001 Meiotic segregation analysis by FISH investigation of spermatozoa of a 46,Y,der(X),t(X;Y)(qter-->p22::q11-->qter) carrier. Cytogenetics and cell genetics 13 11306798
2010 Severe Alport syndrome in a young woman caused by a t(X;1)(q22.3;p36.32) balanced translocation. Pediatric nephrology (Berlin, Germany) 12 20386926
2010 A novel case of t(X;1)(p11.2;p34) in a renal cell carcinoma with TFE3 rearrangement and favorable outcome in a 57-year-old patient. Cancer genetics and cytogenetics 12 20620589
2004 Multicolor fluorescence in situ hybridization analysis of a synovial sarcoma of the larynx with a t(X;18)(p11.2;q11.2) and trisomies 2 and 8. Cancer genetics and cytogenetics 12 15325093
1999 Nuclear genes from Tx CMS maintainer lines are unable to maintain atp6 RNA editing in any anther cell-type in the sorghum bicolor A3 cytoplasm. Current genetics 12 10447596
1993 Identification of a yeast artificial chromosome that spans the human papillary renal cell carcinoma-associated t(X;1) breakpoint in Xp11.2. Cancer genetics and cytogenetics 11 8281521

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