CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase))

2007-11-01 Yatender Kumar , Vegesna Radha , Ghanshyam Swarup Affiliation

Centre for Cellular, Molecular Biology, Uppal Road, Hyderabad - 500 007, INDIA

Identity

HGNC

CASP1

LOCATION

11q22.3

IMAGE

LOCUSID

834

ALIAS

ICE,IL1BC,P45

FUSION GENES

Show Gene Fusions

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.

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.

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.

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.

Homology

CARD of caspase-1 bears significant homology with the CARDs of Caspase-4, Caspase-5, SFRS2IP/Caspase-11, Caspase-12, ICEBERG, Nod1, NLRC4, NEDD2, cIAP2, cIAP3 and ced3.

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.

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

Gene ID	Transcript ID	Uniprot
ENSG00000137752	ENST00000353247	P29466
ENSG00000137752	ENST00000436863	P29466
ENSG00000137752	ENST00000446369	P29466
ENSG00000137752	ENST00000525825	P29466
ENSG00000137752	ENST00000526568	P29466
ENSG00000137752	ENST00000527979	G3V169
ENSG00000137752	ENST00000528974	B4DVD8
ENSG00000137752	ENST00000529871	Q5FBZ0
ENSG00000137752	ENST00000531166	P29466
ENSG00000137752	ENST00000532439	H0YEC7
ENSG00000137752	ENST00000533400	P29466
ENSG00000137752	ENST00000534497	P29466
ENSG00000137752	ENST00000640184	A0A1W2PRX7

Expression (GTEx)

100

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Amyotrophic lateral sclerosis (ALS)	KEGG	ko05014
Amyotrophic lateral sclerosis (ALS)	KEGG	hsa05014
NOD-like receptor signaling pathway	KEGG	ko04621
NOD-like receptor signaling pathway	KEGG	hsa04621
Cytosolic DNA-sensing pathway	KEGG	ko04623
Cytosolic DNA-sensing pathway	KEGG	hsa04623
Influenza A	KEGG	ko05164
Influenza A	KEGG	hsa05164
Pertussis	KEGG	ko05133
Pertussis	KEGG	hsa05133
Salmonella infection	KEGG	ko05132
Salmonella infection	KEGG	hsa05132
Legionellosis	KEGG	ko05134
Legionellosis	KEGG	hsa05134
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	REACTOME	R-HSA-168643
NOD1/2 Signaling Pathway	REACTOME	R-HSA-168638
Inflammasomes	REACTOME	R-HSA-622312
The NLRP3 inflammasome	REACTOME	R-HSA-844456
The IPAF inflammasome	REACTOME	R-HSA-844623
The AIM2 inflammasome	REACTOME	R-HSA-844615
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-1 processing	REACTOME	R-HSA-448706
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
TP53 Regulates Transcription of Cell Death Genes	REACTOME	R-HSA-5633008
TP53 Regulates Transcription of Caspase Activators and Caspases	REACTOME	R-HSA-6803207

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
12191486	2002	The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.	1466
17036048	2006	Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.	495
24356306	2014	Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.	346
27669650	2016	Mechanism and Regulation of NLRP3 Inflammasome Activation.	330
18329368	2008	Active caspase-1 is a regulator of unconventional protein secretion.	307
19439663	2009	The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.	211
11967258	2002	The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.	150
12019269	2002	PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing.	119
17959595	2007	The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock.	119
16785446	2006	The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production.	114

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