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Protein

Caspase-4

Gene

CASP4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Inflammatory caspase (PubMed:7797510, PubMed:23516580, PubMed:25119034). Essential effector of NLRP3 inflammasome-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:22246630, PubMed:26174085, PubMed:26173988, PubMed:26508369, PubMed:25964352). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, and IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:24879791, PubMed:25964352). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection (PubMed:25121752). In later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).15 Publications

Catalytic activityi

Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp-|- but also cleaves at Asp-Glu-Val-Asp-|-.1 Publication

Enzyme regulationi

Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner (PubMed:25119034).1 Publication
(Microbial infection) Inhibited by the effector protein NleF produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580).1 Publication

Kineticsi

Values obtained using the partial C-terminal enzyme sequence of 105-377.1 Publication
  1. KM=681 µM for synthetic peptide acetyl-YVAD-p-nitroanilide1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei210By similarity1
    Active sitei2584 Publications1

    GO - Molecular functioni

    • CARD domain binding Source: UniProtKB
    • cysteine-type endopeptidase activity Source: UniProtKB
    • cysteine-type endopeptidase activity involved in apoptotic process Source: GO_Central

    GO - Biological processi

    • apoptotic process Source: ProtInc
    • cellular response to amyloid-beta Source: ParkinsonsUK-UCL
    • inflammatory response Source: UniProtKB-KW
    • innate immune response Source: UniProtKB-KW
    • intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
    • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
    • positive regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
    • proteolysis Source: ProtInc
    • regulation of apoptotic process Source: InterPro
    • regulation of inflammatory response Source: GO_Central

    Keywordsi

    Molecular functionHydrolase, Protease, Thiol protease
    Biological processImmunity, Inflammatory response, Innate immunity, Necrosis

    Enzyme and pathway databases

    BRENDAi3.4.22.57 2681
    ReactomeiR-HSA-168638 NOD1/2 Signaling Pathway
    SABIO-RKiP49662

    Protein family/group databases

    MEROPSiC14.007

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Caspase-4 (EC:3.4.22.571 Publication)
    Short name:
    CASP-4
    Alternative name(s):
    ICE and Ced-3 homolog 21 Publication
    Short name:
    ICH-21 Publication
    ICE(rel)-II1 Publication
    Mih11 Publication
    Protease TX1 Publication
    Cleaved into the following 2 chains:
    Gene namesi
    Name:CASP4
    Synonyms:ICH2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 11

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000196954.12
    HGNCiHGNC:1505 CASP4
    MIMi602664 gene
    neXtProtiNX_P49662

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Endoplasmic reticulum, Inflammasome, Membrane, Mitochondrion, Secreted

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi258C → A: Loss of enzymatic activity. Loss of LPS-induced pyroptosis. No effect on the interaction with LPS. Decrease in cell death induced by TMEM214 overexpression. Does not support IL1B and IL18 secretion following UVB irradiation. 4 Publications1
    Mutagenesisi258C → S: Loss of autocatalysis. 1 Publication1

    Organism-specific databases

    DisGeNETi837
    OpenTargetsiENSG00000196954
    PharmGKBiPA26088

    Chemistry databases

    ChEMBLiCHEMBL2226
    GuidetoPHARMACOLOGYi1620

    Polymorphism and mutation databases

    BioMutaiCASP4
    DMDMi1352420

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    PropeptideiPRO_00000045961 – ?80Sequence analysisAdd BLAST80
    ChainiPRO_0000004597?81 – 270Caspase-4 subunit 1Add BLAST190
    PropeptideiPRO_0000004598271 – 289Sequence analysis1 PublicationAdd BLAST19
    ChainiPRO_0000004599290 – 377Caspase-4 subunit 2Add BLAST88
    Isoform 2 (identifier: P49662-2)
    Initiator methionineiRemovedCombined sourcesCurated

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei83PhosphoserineCombined sources1
    Isoform 2 (identifier: P49662-2)
    Modified residuei2N-acetylalanineCombined sourcesCurated1

    Post-translational modificationi

    In response to activation signals, including endoplasmic reticulum stress or treatment with amyloid-beta A4 protein fragments (such as amyloid-beta protein 40), undergoes autoproteolytic cleavage.3 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sitei289 – 290Cleavage; by autolysis1 Publication2

    Keywords - PTMi

    Acetylation, Phosphoprotein, Zymogen

    Proteomic databases

    EPDiP49662
    MaxQBiP49662
    PaxDbiP49662
    PeptideAtlasiP49662
    PRIDEiP49662
    ProteomicsDBi56043
    56044 [P49662-2]

    PTM databases

    iPTMnetiP49662
    PhosphoSitePlusiP49662

    Expressioni

    Tissue specificityi

    Widely expressed, including in keratinocytes and colonic and small intestinal epithelial cells (at protein level). Not detected in brain.6 Publications

    Inductioni

    In peripheral blood mononuclear cells and purified monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and interferon-beta/IFNB1 at the mRNA level (PubMed:16893518, PubMed:24879791). However, this increase is not observed at the protein level, which remains constant in monocytes and other cell types following LPS treatment (PubMed:25121752) (PubMed:26508369). In monocyte-derived macrophages, some up-regulation at the protein level is observed following treatment with LPS and IFNB1 (PubMed:25964352). In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65 at both mRNA and protein levels.3 Publications

    Gene expression databases

    BgeeiENSG00000196954
    CleanExiHS_CASP4
    ExpressionAtlasiP49662 baseline and differential
    GenevisibleiP49662 HS

    Organism-specific databases

    HPAiCAB037167
    HPA027588

    Interactioni

    Subunit structurei

    Upon direct LPS-binding, forms large homooligomers, resulting in its activation. These oligomers are often referred to as 'non-canonical inflammasomes' (PubMed:25119034). Active as a heterotetramer consisting of two anti-parallel arranged heterodimers, each one formed by a small and a large subunit (By similarity). In its precursor form, interacts with TMEM214; this interaction is required for association with the endoplasmic reticulum membrane (PubMed:23661706). Interacts with CASP1 (PubMed:22246630). Interacts with NOD2 (PubMed:18511561).By similarity4 Publications
    (Microbial infection) Interacts with NleF protein from pathogenic E.coli; this interaction leads to enzyme inhibition.1 Publication

    GO - Molecular functioni

    • CARD domain binding Source: UniProtKB

    Protein-protein interaction databases

    BioGridi107287, 34 interactors
    DIPiDIP-44806N
    IntActiP49662, 41 interactors
    STRINGi9606.ENSP00000388566

    Chemistry databases

    BindingDBiP49662

    Structurei

    3D structure databases

    ProteinModelPortaliP49662
    SMRiP49662
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini1 – 91CARDPROSITE-ProRule annotationAdd BLAST91

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni1 – 59Required for LPS-bindingBy similarityAdd BLAST59

    Domaini

    The CARD domain mediates LPS recognition and homooligomerization.1 Publication

    Sequence similaritiesi

    Belongs to the peptidase C14A family.Curated

    Phylogenomic databases

    eggNOGiKOG3573 Eukaryota
    ENOG410ZQIE LUCA
    GeneTreeiENSGT00910000144131
    HOGENOMiHOG000234399
    HOVERGENiHBG076981
    InParanoidiP49662
    KOiK04394
    OMAiFFNIDQI
    OrthoDBiEOG091G07NO
    PhylomeDBiP49662
    TreeFamiTF102023

    Family and domain databases

    CDDicd00032 CASc, 1 hit
    InterProiView protein in InterPro
    IPR001315 CARD
    IPR029030 Caspase-like_dom_sf
    IPR033139 Caspase_cys_AS
    IPR016129 Caspase_his_AS
    IPR011029 DEATH-like_dom_sf
    IPR002138 Pept_C14_p10
    IPR001309 Pept_C14_p20
    IPR015917 Pept_C14A
    PfamiView protein in Pfam
    PF00619 CARD, 1 hit
    PRINTSiPR00376 IL1BCENZYME
    SMARTiView protein in SMART
    SM00114 CARD, 1 hit
    SM00115 CASc, 1 hit
    SUPFAMiSSF47986 SSF47986, 1 hit
    SSF52129 SSF52129, 1 hit
    PROSITEiView protein in PROSITE
    PS50209 CARD, 1 hit
    PS01122 CASPASE_CYS, 1 hit
    PS01121 CASPASE_HIS, 1 hit
    PS50207 CASPASE_P10, 1 hit
    PS50208 CASPASE_P20, 1 hit

    Sequences (5)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P49662-1) [UniParc]FASTAAdd to basket
    Also known as: Alpha

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MAEGNHRKKP LKVLESLGKD FLTGVLDNLV EQNVLNWKEE EKKKYYDAKT
    60 70 80 90 100
    EDKVRVMADS MQEKQRMAGQ MLLQTFFNID QISPNKKAHP NMEAGPPESG
    110 120 130 140 150
    ESTDALKLCP HEEFLRLCKE RAEEIYPIKE RNNRTRLALI ICNTEFDHLP
    160 170 180 190 200
    PRNGADFDIT GMKELLEGLD YSVDVEENLT ARDMESALRA FATRPEHKSS
    210 220 230 240 250
    DSTFLVLMSH GILEGICGTV HDEKKPDVLL YDTIFQIFNN RNCLSLKDKP
    260 270 280 290 300
    KVIIVQACRG ANRGELWVRD SPASLEVASS QSSENLEEDA VYKTHVEKDF
    310 320 330 340 350
    IAFCSSTPHN VSWRDSTMGS IFITQLITCF QKYSWCCHLE EVFRKVQQSF
    360 370
    ETPRAKAQMP TIERLSMTRY FYLFPGN
    Length:377
    Mass (Da):43,262
    Last modified:February 1, 1996 - v1
    Checksum:iDC7CCEC6E9D483EB
    GO
    Isoform 2 (identifier: P49662-2) [UniParc]FASTAAdd to basket
    Also known as: Gamma, mih1-beta

    The sequence of this isoform differs from the canonical sequence as follows:
         1-56: Missing.

    Show »
    Length:321
    Mass (Da):36,705
    Checksum:i7336654FD603B65A
    GO
    Isoform 3 (identifier: P49662-3) [UniParc]FASTAAdd to basket
    Also known as: mih1-delta

    The sequence of this isoform differs from the canonical sequence as follows:
         88-116: AHPNMEAGPPESGESTDALKLCPHEEFLR → GDKLGHRGRNHNLCSAISCSSSEYGGWTT
         117-377: Missing.

    Note: May be due to competing acceptor splice site. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.Curated
    Show »
    Length:116
    Mass (Da):13,264
    Checksum:iFD9ED1FF1DF981D3
    GO
    Isoform 4 (identifier: P49662-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         261-263: ANR → GEC
         264-377: Missing.

    Note: No experimental confirmation available.Curated
    Show »
    Length:263
    Mass (Da):30,000
    Checksum:iFED10278B701F0F0
    GO
    Isoform 5 (identifier: P49662-5) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         125-157: IYPIKERNNRTRLALIICNTEFDHLPPRNGADF → VLCYLYEIEKKEEISLLSFSAPFLTALNDWGWG
         158-377: Missing.

    Note: No experimental confirmation available.Curated
    Show »
    Length:157
    Mass (Da):18,111
    Checksum:i65936259DD31435E
    GO

    Sequence cautioni

    Isoform 2 : The sequence AAC99851 differs from that shown. Reason: Frameshift at position 19.Combined sourcesCurated
    The sequence AAC99854 differs from that shown. Reason: Erroneous translation. Erroneous CDS prediction.Curated
    The sequence EAW67050 differs from that shown. Reason: Erroneous gene model prediction.Curated

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_06108147D → N. Corresponds to variant dbSNP:rs56226603Ensembl.1
    Natural variantiVAR_075654134R → C1 PublicationCorresponds to variant dbSNP:rs181090259Ensembl.1
    Natural variantiVAR_061082284E → D. Corresponds to variant dbSNP:rs55901059Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0434951 – 56Missing in isoform 2. 1 PublicationAdd BLAST56
    Alternative sequenceiVSP_05817788 – 116AHPNM…EEFLR → GDKLGHRGRNHNLCSAISCS SSEYGGWTT in isoform 3. 1 PublicationAdd BLAST29
    Alternative sequenceiVSP_058178117 – 377Missing in isoform 3. 1 PublicationAdd BLAST261
    Alternative sequenceiVSP_058179125 – 157IYPIK…NGADF → VLCYLYEIEKKEEISLLSFS APFLTALNDWGWG in isoform 5. 1 PublicationAdd BLAST33
    Alternative sequenceiVSP_058180158 – 377Missing in isoform 5. 1 PublicationAdd BLAST220
    Alternative sequenceiVSP_058181261 – 263ANR → GEC in isoform 4. 2 Publications3
    Alternative sequenceiVSP_058182264 – 377Missing in isoform 4. 2 PublicationsAdd BLAST114

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    Z48810 mRNA Translation: CAA88750.1
    U28014 mRNA Translation: AAA75171.1
    U25804 mRNA Translation: AAA86890.1
    U28976 mRNA Translation: AAC99850.1
    U28977 mRNA Translation: AAC99851.1 Frameshift.
    U28978 mRNA Translation: AAC99852.1
    U28979 mRNA Translation: AAC99853.1
    U28979 mRNA Translation: AAC99854.1 Sequence problems.
    AK057094 mRNA Translation: BAG51861.1
    AK296081 mRNA Translation: BAG58837.1
    AK304222 mRNA Translation: BAG65094.1
    EF636667 Genomic DNA Translation: ABR09278.1
    AP001153 Genomic DNA No translation available.
    AP002004 Genomic DNA No translation available.
    CH471065 Genomic DNA Translation: EAW67050.1 Sequence problems.
    CH471065 Genomic DNA Translation: EAW67051.1
    CH471065 Genomic DNA Translation: EAW67052.1
    BC017839 mRNA Translation: AAH17839.1
    AL050391 mRNA Translation: CAB43686.2
    CCDSiCCDS41704.1 [P49662-2]
    CCDS8327.1 [P49662-1]
    PIRiA57511
    RefSeqiNP_001216.1, NM_001225.3 [P49662-1]
    NP_150649.1, NM_033306.2 [P49662-2]
    XP_011541321.1, XM_011543019.1
    XP_016873886.1, XM_017018397.1
    UniGeneiHs.138378

    Genome annotation databases

    EnsembliENST00000393150; ENSP00000376857; ENSG00000196954 [P49662-2]
    ENST00000444739; ENSP00000388566; ENSG00000196954 [P49662-1]
    GeneIDi837
    KEGGihsa:837
    UCSCiuc001pib.2 human [P49662-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiCASP4_HUMAN
    AccessioniPrimary (citable) accession number: P49662
    Secondary accession number(s): A2NHL8
    , A2NHL9, A2NHM0, B3KPZ9, B4DJH5, B4E2D2, O95601, Q7KYX7, Q9UG96
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: February 1, 1996
    Last modified: July 18, 2018
    This is version 182 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Peptidase families
      Classification of peptidase families and list of entries
    6. SIMILARITY comments
      Index of protein domains and families

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