CASP4_BOVIN
ID CASP4_BOVIN Reviewed; 377 AA.
AC Q5E9C1;
DT 27-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Caspase-4;
DE Short=CASP-4;
DE EC=3.4.22.57 {ECO:0000250|UniProtKB:P49662};
DE Contains:
DE RecName: Full=Caspase-4 subunit p10 {ECO:0000250|UniProtKB:P49662};
DE Contains:
DE RecName: Full=Caspase-4 subunit p20 {ECO:0000250|UniProtKB:P49662};
DE Flags: Precursor;
GN Name=CASP4;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16305752; DOI=10.1186/1471-2164-6-166;
RA Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
RA Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
RT "Characterization of 954 bovine full-CDS cDNA sequences.";
RL BMC Genomics 6:166-166(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Hypothalamus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Inflammatory caspase that acts as an essential effector of
CC the NLRP3 and NLRP6 inflammasomes by mediating lipopolysaccharide
CC (LPS)-induced pyroptosis. Thiol protease that cleaves a tetrapeptide
CC after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD
CC and IL18. Required for innate immunity to cytosolic, but not vacuolar,
CC bacteria. Plays a key role in NLRP3-dependent CASP1 activation and IL1B
CC and IL18 secretion in response to non-canonical activators, such as UVB
CC radiation, cholera enterotoxin subunit B and cytosolic LPS. Activated
CC by direct binding to LPS without the need of an upstream sensor.
CC Involved in NLRP6 inflammasome-dependent activation in response to
CC lipoteichoic acid (LTA), a cell-wall component of Gram-positive
CC bacteria, which leads to CASP1 activation and IL1B and IL18 secretion.
CC Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis,
CC through GSDMD cleavage and activation, followed by IL1A, IL18 and HMGB1
CC release in response to non-canonical inflammasome activators. Plays a
CC crucial role in the restriction of Salmonella typhimurium replication
CC in colonic epithelial cells during infection: in later stages of the
CC infection, LPS from cytosolic Salmonella triggers CASP4 activation,
CC which catalyzes cleavage of GSDMD, resulting in pyroptosis of infected
CC cells and their extrusion into the gut lumen, as well as in IL18
CC secretion. Cleavage of GSDMD is not strictly dependent on the consensus
CC cleavage site but depends on an exosite interface on CASP4 that
CC recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part.
CC Pyroptosis limits bacterial replication, while cytokine secretion
CC promotes the recruitment and activation of immune cells and triggers
CC mucosal inflammation (By similarity). Involved in LPS-induced IL6
CC secretion; this activity may not require caspase enzymatic activity.
CC Catalyzes cleavage and maturation of IL18 (By similarity). In contrast,
CC it does not directly process IL1B. During non-canonical inflammasome
CC activation, cuts CGAS and may play a role in the regulation of
CC antiviral innate immune activation (By similarity).
CC {ECO:0000250|UniProtKB:P49662, ECO:0000250|UniProtKB:P70343}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at the P1 position. It has a
CC preferred cleavage sequence of Tyr-Val-Ala-Asp-|- but also cleaves at
CC Asp-Glu-Val-Asp-|-.; EC=3.4.22.57;
CC Evidence={ECO:0000250|UniProtKB:P49662};
CC -!- ACTIVITY REGULATION: Activated by homooligomerization induced by direct
CC binding to cytosolic LPS, in a TLR4-independent manner.
CC {ECO:0000250|UniProtKB:P70343}.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a
CC 10 kDa (Caspase-4 subunit p10) subunit. Upon direct LPS-binding, forms
CC large homooligomers, resulting in its activation. These oligomers are
CC often referred to as 'non-canonical inflammasomes' (By similarity). In
CC its precursor form, interacts with TMEM214; this interaction is
CC required for association with the endoplasmic reticulum membrane.
CC Interacts with CASP1. Interacts with NOD2. Interacts with Serpinb1a,
CC Serpinb1b and Serpinb1c; these interactions regulate CASP4 activity (By
CC similarity). {ECO:0000250|UniProtKB:P49662,
CC ECO:0000250|UniProtKB:P70343}.
CC -!- SUBUNIT: [Caspase-4 subunit p20]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC {ECO:0000250|UniProtKB:P70343}.
CC -!- SUBUNIT: [Caspase-4 subunit p10]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC {ECO:0000250|UniProtKB:P70343}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P49662}. Cytoplasm
CC {ECO:0000250|UniProtKB:P70343}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P49662}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P49662}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:P49662}. Mitochondrion
CC {ECO:0000250|UniProtKB:P49662}. Inflammasome
CC {ECO:0000250|UniProtKB:P70343}. Secreted
CC {ECO:0000250|UniProtKB:P49662}. Note=Predominantly localizes to the
CC endoplasmic reticulum (ER). Association with the ER membrane requires
CC TMEM214. Released in the extracellular milieu by keratinocytes
CC following UVB irradiation. {ECO:0000250|UniProtKB:P49662}.
CC -!- DOMAIN: The CARD domain mediates LPS recognition and
CC homooligomerization. {ECO:0000250|UniProtKB:P70343}.
CC -!- PTM: In response to activation signals, including cholera enterotoxin
CC subunit B, infection by E. coli or S. typhimurium or endoplasmic
CC reticulum stress, undergoes autoproteolytic cleavage.
CC {ECO:0000250|UniProtKB:P70343}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; BT020999; AAX09016.1; -; mRNA.
DR EMBL; BC112708; AAI12709.1; -; mRNA.
DR RefSeq; NP_788811.1; NM_176638.5.
DR AlphaFoldDB; Q5E9C1; -.
DR SMR; Q5E9C1; -.
DR STRING; 9913.ENSBTAP00000027820; -.
DR MEROPS; C14.017; -.
DR PaxDb; Q5E9C1; -.
DR PRIDE; Q5E9C1; -.
DR Ensembl; ENSBTAT00000027820; ENSBTAP00000027820; ENSBTAG00000020884.
DR GeneID; 338039; -.
DR KEGG; bta:338039; -.
DR CTD; 837; -.
DR VEuPathDB; HostDB:ENSBTAG00000020884; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000161497; -.
DR OMA; KAHLNME; -.
DR OrthoDB; 1327703at2759; -.
DR Proteomes; UP000009136; Chromosome 15.
DR Bgee; ENSBTAG00000020884; Expressed in neutrophil and 103 other tissues.
DR ExpressionAtlas; Q5E9C1; baseline and differential.
DR GO; GO:0097169; C:AIM2 inflammasome complex; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0072557; C:IPAF inflammasome complex; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IBA:GO_Central.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0042742; P:defense response to bacterium; ISS:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:2000494; P:positive regulation of interleukin-18-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
DR CDD; cd00032; CASc; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR033139; Caspase_cys_AS.
DR InterPro; IPR016129; Caspase_his_AS.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR Pfam; PF00619; CARD; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00114; CARD; 1.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 2: Evidence at transcript level;
KW Cytoplasm; Endoplasmic reticulum; Hydrolase; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Membrane; Mitochondrion; Necrosis;
KW Phosphoprotein; Protease; Reference proteome; Secreted; Thiol protease;
KW Zymogen.
FT PROPEP 1..?80
FT /evidence="ECO:0000255"
FT /id="PRO_0000244735"
FT CHAIN ?81..270
FT /note="Caspase-4 subunit p20"
FT /evidence="ECO:0000250|UniProtKB:P49662"
FT /id="PRO_0000244736"
FT PROPEP 271..289
FT /evidence="ECO:0000255"
FT /id="PRO_0000244737"
FT CHAIN 290..377
FT /note="Caspase-4 subunit p10"
FT /evidence="ECO:0000250|UniProtKB:P49662"
FT /id="PRO_0000244738"
FT DOMAIN 1..91
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..59
FT /note="Required for LPS-binding"
FT /evidence="ECO:0000250|UniProtKB:P70343"
FT ACT_SITE 210
FT /evidence="ECO:0000250|UniProtKB:P29466"
FT ACT_SITE 258
FT /evidence="ECO:0000250|UniProtKB:P49662"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49662"
SQ SEQUENCE 377 AA; 43012 MW; 959A59424DAECBF4 CRC64;
MAEDKHNKNP LKMLESLGKE LISGLLDDFV EKNVLKLEEE EKKKIYDAKL QDKARVLVDS
IRQKNQEAGQ VFVQTFLNID KNSTSIKAPE ETVAGPDESV GSAATLKLCP HEEFLKLCKE
RAGEIYPIKE RKDRTRLALI ICNTEFDHMP PRNGAALDIL GMKQLLEGLG YTVEVEEKLT
ARDMESVLWK FAAREEHKSS DSTFLVFMSH GILDGICGTM HSEEEPDVLP YDTIFRTFNN
RNCLSLKDKP KVIIVQACRG ANRGELWVSD SPPALADSFS QSSENLEEDA VYKTHVEKDF
IAFCSSTPHN VSWRDIKKGS LFITRLITCF QKYAWCCHLE EVFRKVQQSF EKPNVKAQMP
TVERLSMTRY FYLFPGN
