CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase))
2007-11-01 Yatender Kumar , Vegesna Radha , Ghanshyam Swarup AffiliationCentre for Cellular, Molecular Biology, Uppal Road, Hyderabad - 500 007, INDIA
Identity
HGNC
LOCATION
11q22.3
IMAGE
LOCUSID
ALIAS
ICE,IL1BC,P45
FUSION GENES
DNA/RNA
Description
The human caspase-1 gene is comprised of 10 exons, spanning 10.6kb on chromosome 11q22.2-q22.3.
Transcription
Six alternatively spliced forms of caspase-1 have been identified in Homo sapiens.
The longest termed CASP1alpha is 1364bp with an ORF encoding 404 amino acids (aa) and is the most predominant isoform. CASP1beta is 1185bp, lacks entire exon3 (275-338bp; 92-112aa), ORF encoding 383aa. CASP1gamma is 969bp, lacks most of exon2 and entire exon3 (59-338bp; 20-112aa), ORF encoding 291aa. CASP1delta is 825bp, lacks entire exon7 (863-1006bp; 288-335aa), ORF encoding 356aa. CASP1epsilon is 300bp, lacks most of exon2 and exon3 exon7 (59-1006bp; 20-335aa), ORF encoding 98aa. CASP1zeta is 1131bp, missing 79bp in prodomain of caspase-1, ORF encoding 365aa. Among these alpha, beta, gamma and zeta forms are proteolytically active and can induce apoptosis. As delta and epsilon lack part of the catalytic domain, they do not induce apoptosis and serve as inhibitors of caspase-1 when overexpressed.
The longest termed CASP1alpha is 1364bp with an ORF encoding 404 amino acids (aa) and is the most predominant isoform. CASP1beta is 1185bp, lacks entire exon3 (275-338bp; 92-112aa), ORF encoding 383aa. CASP1gamma is 969bp, lacks most of exon2 and entire exon3 (59-338bp; 20-112aa), ORF encoding 291aa. CASP1delta is 825bp, lacks entire exon7 (863-1006bp; 288-335aa), ORF encoding 356aa. CASP1epsilon is 300bp, lacks most of exon2 and exon3 exon7 (59-1006bp; 20-335aa), ORF encoding 98aa. CASP1zeta is 1131bp, missing 79bp in prodomain of caspase-1, ORF encoding 365aa. Among these alpha, beta, gamma and zeta forms are proteolytically active and can induce apoptosis. As delta and epsilon lack part of the catalytic domain, they do not induce apoptosis and serve as inhibitors of caspase-1 when overexpressed.
Pseudogene
COP (Card Only Protein)
Proteins
Description
Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspases-4, caspases-5, and caspases-12. It is also involved in some forms of apoptosis. Caspase-1 protein consists of an N-terminal CARD (caspase activation and recruitment domain), a large P20 subunit and a small P10 subunit. Due to its long N-terminal prodomain, caspase-1 belongs to the initiator group of caspases and is therefore suspected to act proximally in a caspase activation cascade leading to apoptosis.
Caspase-1 is synthesized as a proenzyme of 45kDa, which undergoes proteolytic cleavage at Asp residues to produce the active enzyme. The active caspase-1 enzyme is a hetrotetramer comprised of two P20 and two P10 subunits. The catalytic site is formed by amino acids from both P20 and P10 subunits, with the active cysteine located within the P20 subunit. Caspase-1 is activated through interactions with other CARD containing proteins such as ASC, RIP2 and NLRC4 via homotypic CARD-CARD interactions. Bacterial and viral proteins like SipB, IpaB, CrmA, and Serp2 which do not contain the CARD domain, also regulate caspase-1. Caspase-1 is activated by phosphorylation at serine 376 residue by PAK1 upon Helicobacter pylori infection.
Caspase-1 is synthesized as a proenzyme of 45kDa, which undergoes proteolytic cleavage at Asp residues to produce the active enzyme. The active caspase-1 enzyme is a hetrotetramer comprised of two P20 and two P10 subunits. The catalytic site is formed by amino acids from both P20 and P10 subunits, with the active cysteine located within the P20 subunit. Caspase-1 is activated through interactions with other CARD containing proteins such as ASC, RIP2 and NLRC4 via homotypic CARD-CARD interactions. Bacterial and viral proteins like SipB, IpaB, CrmA, and Serp2 which do not contain the CARD domain, also regulate caspase-1. Caspase-1 is activated by phosphorylation at serine 376 residue by PAK1 upon Helicobacter pylori infection.
Expression
Caspase-1 is highly expressed in leukocytes, monocytes and epithelial cells.
Caspase-1 gene expression is induced in response to various stimuli such as microbial infections (Mycobacterium avium, Salmonella typhimurium, Legionella pneumophila, Bacillus anthracis, Francisella tularenis and bacterial LPS), cytokines (IFN-gamma and TNF-alpha), growth factors (TGF-beta), and DNA damaging agents (Doxorubicin, UV radiation and Paclitaxel). Levels of caspase-1 mRNA are high in ischemic tissues.
Tumor suppressor p53, p73, SP1, ETS-1, IFT57/HIPPI and IRF-1 activate transcription of full length caspase-1 mRNA by binding to respective sites in the promoter, within a region 550bp upstream of the transcription start site.
Caspase-1 gene expression is induced in response to various stimuli such as microbial infections (Mycobacterium avium, Salmonella typhimurium, Legionella pneumophila, Bacillus anthracis, Francisella tularenis and bacterial LPS), cytokines (IFN-gamma and TNF-alpha), growth factors (TGF-beta), and DNA damaging agents (Doxorubicin, UV radiation and Paclitaxel). Levels of caspase-1 mRNA are high in ischemic tissues.
Tumor suppressor p53, p73, SP1, ETS-1, IFT57/HIPPI and IRF-1 activate transcription of full length caspase-1 mRNA by binding to respective sites in the promoter, within a region 550bp upstream of the transcription start site.
Localisation
Predominantly cytoplasmic. See Table-1 and Table-2.
Function
The adaptor molecules ASC, NLRC4 and Cryopyrin/Nalp3 regulate caspase-1 within a multiprotein complex known as the "Inflammasome". Caspase-1 activation results in cleavage and activation of proinflammatory cytokines such as IL-1beta and IL-18. Caspase-1 deficient mice have a defect in the maturation of proIL-1beta and are resistant to the lethal effect of endotoxins. Various pathogens such as S.typhimurium (TypeIII secretion), L.pneumophila (Type IV secretion), B.anthracis (Lethal Toxin), F.tularenis activate caspase-1 through "inflammasomes". Caspase-1 activation also occurs upon exposure to bacterial RNA, imidazoquilone compounds, LPS, extracellular ATP, muramyl dipeptide (MDP), monosodium urate, calcium pyrophosphate dehydrate and other TLR ligands via "inflammasomes". In addition to bacterial pathogens, viral infection also induces caspase-1 activation. Caspase-1 acts apically in neuronal cell death pathways induced by hypoxia and ischaemia. Caspase-1 is also involved in p53-mediated apoptosis in a cell type specific manner. Caspase-1 sensitizes cells to death induced by agents like Fas ligand, radiation and cisplatin. Caspase-1 stimulates membrane biogenesis to repair damage caused by pore-forming toxins, thereby promoting host cell survival.
Mutations
Germinal
Not Known
Somatic
Not Known
Implicated in
Entity name
Various Diseases
Disease
In diseases such as ischemic and hypoxia induced brain injury, acute bacterial meningitis, ischemia of the heart and kidney. A role for caspase-1 has been implicated in Amyotrophic Lateral Sclerosis, Huntingtons disease, Parkinsons disease, Crohns disease, Age-related cognitive dysfunctions, spinalcord inflammation and gout. Caspase1- activation is enhanced in patients with CINCA syndrome.
Entity name
Cancers
Disease
In ovarian Cancer and stomach Cancer: there is a decreased expression of caspase-1.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 15030775 | 2004 | NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. | Agostini L et al |
| 7876192 | 1995 | Cloning and expression of four novel isoforms of human interleukin-1 beta converting enzyme with different apoptotic activities. | Alnemri ES et al |
| 15561713 | 2005 | NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. | Basak C et al |
| 2784432 | 1989 | A pre-aspartate-specific protease from human leukocytes that cleaves pro-interleukin-1 beta. | Black RA et al |
| 16778130 | 2006 | Haplotypes of the caspase-1 gene, plasma caspase-1 levels, and cardiovascular risk. | Blankenberg S et al |
| 11029688 | 2000 | Salmonella induces macrophage death by caspase-1-dependent necrosis. | Brennan MA et al |
| 15456791 | 2004 | PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. | Bruey JM et al |
| 8034320 | 1994 | Molecular characterization of the gene for human interleukin-1 beta converting enzyme (IL1BC). | Cerretti DP et al |
| 16785446 | 2006 | The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. | Chae JJ et al |
| 15010463 | 2004 | Anthrax lethal toxin rapidly activates caspase-1/ICE and induces extracellular release of interleukin (IL)-1beta and IL-18. | Cordoba-Rodriguez R et al |
| 10233883 | 1999 | Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. | Dai C et al |
| 11536016 | 2001 | Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. | Druilhe A et al |
| 7536900 | 1995 | Involvement of an ICE-like protease in Fas-mediated apoptosis. | Enari M et al |
| 16204022 | 2005 | Caspase-1alpha is down-regulated in human ovarian cancer cells and the overexpression of caspase-1alpha induces apoptosis. | Feng Q et al |
| 16648852 | 2006 | Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. | Franchi L et al |
| 10203693 | 1998 | ICE, neuronal apoptosis and neurodegeneration. | Friedlander RM et al |
| 14598973 | 2003 | Impaired interleukin-1beta converting enzyme (ICE) activity in patients with pulmonary tuberculosis. | Fujiuchi S et al |
| 17763411 | 2007 | Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. | Gattorno M et al |
| 17593876 | 2007 | Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. | Gemma C et al |
| 16123779 | 2006 | Caspase-1 activation of caspase-6 in human apoptotic neurons. | Guo H et al |
| 12459463 | 2002 | A nuclear protein tyrosine phosphatase activates p53 and induces caspase-1-dependent apoptosis. | Gupta S et al |
| 16990137 | 2006 | Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. | Gurcel L et al |
| 10051653 | 1999 | The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. | Hersh D et al |
| 9393811 | 1997 | The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages. | Hilbi H et al |
| 9830039 | 1998 | Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. | Hilbi H et al |
| 11051551 | 2000 | ICEBERG: a novel inhibitor of interleukin-1beta generation. | Humke EW et al |
| 16135520 | 2005 | Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin. | Jain N et al |
| 17725714 | 2007 | Tumor necrosis factor-alpha-induced caspase-1 gene expression. Role of p73. | Jain N et al |
| 15809717 | 2005 | Loss of caspase-1 gene expression in human gastric carcinomas and cell lines. | Jee CD et al |
| 12692130 | 2003 | Caspase-1 and caspase-8 cleave and inactivate cellular parkin. | Kahns S et al |
| 16407888 | 2006 | Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. | Kanneganti TD et al |
| 8700913 | 1996 | Cleavage of actin by interleukin 1 beta-converting enzyme to reverse DNase I inhibition. | Kayalar C et al |
| 2787508 | 1989 | Identification of a monocyte specific pre-interleukin 1 beta convertase activity. | Kostura MJ et al |
| 7535475 | 1995 | Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. | Kuida K et al |
| 9875225 | 1998 | Cleavage of human cytosolic phospholipase A2 by caspase-1 (ICE) and caspase-8 (FLICE). | Lüschen S et al |
| 10601248 | 1999 | ATP treatment of human monocytes promotes caspase-1 maturation and externalization. | Laliberte RE et al |
| 15383541 | 2004 | INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. | Lamkanfi M et al |
| 16717117 | 2006 | Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. | Lara-Tejero M et al |
| 11432859 | 2001 | Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. | Lee SH et al |
| 16895974 | 2006 | Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation. | Li H et al |
| 10764647 | 2000 | Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. | Li M et al |
| 7859282 | 1995 | Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. | Li P et al |
| 10532634 | 1999 | Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. | Liu XH et al |
| 17173859 | 2007 | Interaction of HIPPI with putative promoter sequence of caspase-1 in vitro and in vivo. | Majumder P et al |
| 16230474 | 2005 | Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. | Mariathasan S et al |
| 16596269 | 2006 | Caspase-1 as a radio- and chemo-sensitiser in vitro and in vivo. | Martín-Duque P et al |
| 16407889 | 2006 | Gout-associated uric acid crystals activate the NALP3 inflammasome. | Martinon F et al |
| 10337015 | 1999 | Investigation of the expression of IL-1beta converting enzyme and apoptosis in normal and inflammatory bowel disease (IBD) mucosal macrophages. | McAlindon ME et al |
| 9733819 | 1998 | Serp2, an inhibitor of the interleukin-1beta-converting enzyme, is critical in the pathobiology of myxoma virus. | Messud-Petit F et al |
| 16648853 | 2006 | Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. | Miao EA et al |
| 17360653 | 2007 | NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. | Miggin SM et al |
| 8242741 | 1993 | Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. | Miura M et al |
| 11755408 | 2001 | Salmonella-induced macrophage death: the role of caspase-1 in death and inflammation. | Monack DM et al |
| 9250871 | 1997 | Interleukin-1beta-converting enzyme (ICE) and related cell death genes ICErel-II and ICErel-III map to the same PAC clone at band 11q22.2-22.3. | Nasir J et al |
| 10353249 | 1999 | Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. | Ona VO et al |
| 9861044 | 1998 | Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. | Pasinelli P et al |
| 16103071 | 2005 | Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis. | Pei H et al |
| 11226333 | 2001 | Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. | Pomerantz BJ et al |
| 11172034 | 2001 | p53 associates with and targets Delta Np63 into a protein degradation pathway. | Ratovitski EA et al |
| 16861683 | 2006 | Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. | Raupach B et al |
| 1339309 | 1992 | Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. | Ray CA et al |
| 16552444 | 2006 | Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. | Ren T et al |
| 16990128 | 2006 | Caspase-1 builds a new barrier to infection. | Saleh M et al |
| 16286016 | 2005 | IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. | Schmitz J et al |
| 9427712 | 1998 | Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. | Schumann RR et al |
| 17188500 | 2007 | Activation of caspase-1 dependent interleukins in developmental brain trauma. | Sifringer M et al |
| 9421482 | 1998 | The role of interleukin-converting enzyme in Fas-mediated apoptosis in HIV-1 infection. | Sloand EM et al |
| 11967258 | 2002 | The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. | Srinivasula SM et al |
| 16546100 | 2006 | Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. | Sutterwala FS et al |
| 15845887 | 2005 | Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia. | Syed FM et al |
| 16817903 | 2006 | Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis. | Thalappilly S et al |
| 9705938 | 1998 | Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. | Thome M et al |
| 1574116 | 1992 | A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. | Thornberry NA et al |
| 15096476 | 2004 | PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. | Wang Y et al |
| 17850338 | 2008 | Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. | Wickliffe KE et al |
| 8035875 | 1994 | Structure and mechanism of interleukin-1 beta converting enzyme. | Wilson KP et al |
| 11221855 | 2001 | Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. | Winter RN et al |
| 8662843 | 1996 | Activation of the native 45-kDa precursor form of interleukin-1-converting enzyme. | Yamin TT et al |
| 12459189 | 2002 | Nod1, a CARD protein, enhances pro-interleukin-1beta processing through the interaction with pro-caspase-1. | Yoo NJ et al |
| 16037825 | 2006 | Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. | Yu JW et al |
| 16444259 | 2006 | The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. | Zamboni DS et al |
| 14663141 | 2003 | Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. | Zhang WH et al |
| 10903723 | 2000 | Nitric oxide induces thymocyte apoptosis via a caspase-1-dependent mechanism. | Zhou X et al |
Other Information
Locus ID:
NCBI: 834
MIM: 147678
HGNC: 1499
Ensembl: ENSG00000137752
Variants:
dbSNP: 834
ClinVar: 834
TCGA: ENSG00000137752
COSMIC: CASP1
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38221531 | 2024 | Force-induced Caspase-1-dependent pyroptosis regulates orthodontic tooth movement. | 0 |
| 38640260 | 2024 | High expression of CASP1 induces atherosclerosis. | 0 |
| 38221531 | 2024 | Force-induced Caspase-1-dependent pyroptosis regulates orthodontic tooth movement. | 0 |
| 38640260 | 2024 | High expression of CASP1 induces atherosclerosis. | 0 |
| 36512936 | 2023 | Association of caspase-1 gene polymorphisms with rheumatoid arthritis risk in a Chinese Han population. | 0 |
| 36675029 | 2023 | The Mechanism of Osteoprotegerin-Induced Osteoclast Pyroptosis In Vitro. | 3 |
| 36735415 | 2023 | circ_0013613 Promotes the recovery of spinal cord injury by regulating mir-370-3p/caspase1 to regulate neuronal pyroptosis. | 2 |
| 36822457 | 2023 | Overexpression of CASP1 triggers acute promyelocytic leukemia cell pyroptosis and differentiation. | 3 |
| 37067501 | 2023 | Caspase 1 Enhances Transport and Golgi Organization Protein 1 Expression to Promote Procollagen Export From the Endoplasmic Reticulum in Systemic Sclerosis Contributing to Fibrosis. | 1 |
| 37296437 | 2023 | Testis cell pyroptosis mediated by CASP1 and CASP4: possible sertoli cell-only syndrome pathogenesis. | 1 |
| 37946206 | 2023 | Abnormal expression of miR-3653-3p, caspase 1, IL-1β in peripheral blood of schizophrenia. | 0 |
| 38186096 | 2023 | [Expressions of NLRP3, Caspase-1, and GSDMD in nasopharyngeal carcinoma tissue and association with recurrence and metastasis]. | 0 |
| 36512936 | 2023 | Association of caspase-1 gene polymorphisms with rheumatoid arthritis risk in a Chinese Han population. | 0 |
| 36675029 | 2023 | The Mechanism of Osteoprotegerin-Induced Osteoclast Pyroptosis In Vitro. | 3 |
| 36735415 | 2023 | circ_0013613 Promotes the recovery of spinal cord injury by regulating mir-370-3p/caspase1 to regulate neuronal pyroptosis. | 2 |
Citation
Yatender Kumar ; Vegesna Radha ; Ghanshyam Swarup
CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase))
Atlas Genet Cytogenet Oncol Haematol. 2007-11-01
Online version: http://atlasgeneticsoncology.org/gene/145/casp1
