ID   CASPC_HUMAN             Reviewed;         341 AA.
AC   Q6UXS9; D6RBN7;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   12-SEP-2018, sequence version 3.
DT   27-MAR-2024, entry version 150.
DE   RecName: Full=Inactive caspase-12;
DE            Short=CASP-12;
GN   Name=CASP12; ORFNames=UNQ9415/PRO34398;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4; 5; 6; 7 AND 8), FUNCTION,
RP   TISSUE SPECIFICITY, AND VARIANT 125-ARG--ASN-341 DEL.
RC   TISSUE=Lung;
RX   PubMed=12054529; DOI=10.1016/s0006-291x(02)00289-9;
RA   Fischer H., Koenig U., Eckhart L., Tschachler E.;
RT   "Human caspase 12 has acquired deleterious mutations.";
RL   Biochem. Biophys. Res. Commun. 293:722-726(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT 125-ARG--ASN-341
RP   DEL.
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [4]
RP   FUNCTION, POLYMORPHISM, AND VARIANT 125-ARG--ASN-341 DEL.
RX   PubMed=15129283; DOI=10.1038/nature02451;
RA   Saleh M., Vaillancourt J.P., Graham R.K., Huyck M., Srinivasula S.M.,
RA   Alnemri E.S., Steinberg M.H., Nolan V., Baldwin C.T., Hotchkiss R.S.,
RA   Buchman T.G., Zehnbauer B.A., Hayden M.R., Farrer L.A., Roy S.,
RA   Nicholson D.W.;
RT   "Differential modulation of endotoxin responsiveness by human caspase-12
RT   polymorphisms.";
RL   Nature 429:75-79(2004).
RN   [5]
RP   POLYMORPHISM, AND VARIANT 125-ARG--ASN-341 DEL.
RX   PubMed=16917906; DOI=10.1002/humu.9448;
RA   Kachapati K., O'Brien T.R., Bergeron J., Zhang M., Dean M.;
RT   "Population distribution of the functional caspase-12 allele.";
RL   Hum. Mutat. 27:975-975(2006).
RN   [6]
RP   POLYMORPHISM, AND VARIANT 125-ARG--ASN-341 DEL.
RX   PubMed=16532395; DOI=10.1086/503116;
RA   Xue Y., Daly A., Yngvadottir B., Liu M., Coop G., Kim Y., Sabeti P.,
RA   Chen Y., Stalker J., Huckle E., Burton J., Leonard S., Rogers J.,
RA   Tyler-Smith C.;
RT   "Spread of an inactive form of caspase-12 in humans is due to recent
RT   positive selection.";
RL   Am. J. Hum. Genet. 78:659-670(2006).
CC   -!- FUNCTION: May function as a negative regulator of inflammatory
CC       responses and innate immunity. May reduce cytokine release in response
CC       to bacterial lipopolysaccharide during infection. Reduces activation of
CC       NF-kappa-B in response to TNF (PubMed:15129283). May lack protease
CC       activity (Probable). {ECO:0000269|PubMed:15129283,
CC       ECO:0000305|PubMed:12054529}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=8;
CC       Name=1; Synonyms=Epsilon {ECO:0000303|PubMed:12054529}, Gamma
CC       {ECO:0000312|EMBL:AF464191};
CC         IsoId=Q6UXS9-1; Sequence=Displayed;
CC       Name=2; Synonyms=Alpha {ECO:0000303|PubMed:12054529}, Beta
CC       {ECO:0000303|PubMed:12054529};
CC         IsoId=Q6UXS9-2; Sequence=VSP_030954, VSP_030955;
CC       Name=3; Synonyms=Iota {ECO:0000303|PubMed:12054529};
CC         IsoId=Q6UXS9-3; Sequence=VSP_061925, VSP_061927;
CC       Name=4; Synonyms=Zeta {ECO:0000303|PubMed:12054529}, Epsilon
CC       {ECO:0000312|EMBL:AF464192};
CC         IsoId=Q6UXS9-4; Sequence=VSP_061929;
CC       Name=5; Synonyms=Eta {ECO:0000303|PubMed:12054529}, Delta
CC       {ECO:0000312|EMBL:AF464193};
CC         IsoId=Q6UXS9-5; Sequence=VSP_061928;
CC       Name=6; Synonyms=Gamma {ECO:0000303|PubMed:12054529}, Zeta
CC       {ECO:0000312|EMBL:AF486846};
CC         IsoId=Q6UXS9-6; Sequence=VSP_061926;
CC       Name=7; Synonyms=Theta {ECO:0000303|PubMed:12054529}, Eta
CC       {ECO:0000312|EMBL:AF464194};
CC         IsoId=Q6UXS9-7; Sequence=VSP_061927;
CC       Name=8; Synonyms=Delta {ECO:0000303|PubMed:12054529}, Theta
CC       {ECO:0000312|EMBL:AF486847};
CC         IsoId=Q6UXS9-8; Sequence=VSP_061925, VSP_061926;
CC   -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in lung.
CC       {ECO:0000269|PubMed:12054529}.
CC   -!- POLYMORPHISM: The sequence shown in this entry differs from the
CC       translation of the reference genome assembly (GRCh38/hg38) due to a
CC       nonsense variant creating stop codon at position 125 in the reference
CC       genome, giving rise to a truncated protein (Csp12-S) (PubMed:15129283,
CC       PubMed:16917906). The sequence shown in this entry is that of variant
CC       p.Ter125Arg. This variant gives rise to a full length protein (Csp12-
CC       L). It occurs in the human population at a frequence of about 4%
CC       according to the Genome Aggregation Database (gnomAD v3.1.2), with
CC       highest frequency observed in people of African descent (up to 60% in
CC       certain sub-Saharan populations) (PubMed:15129283, PubMed:16917906,
CC       PubMed:16532395). Csp12-L expression may increase the susceptibility to
CC       severe sepsis, and may result in higher mortality rates (up to 3-fold)
CC       once severe sepsis develop (PubMed:15129283).
CC       {ECO:0000269|PubMed:15129283, ECO:0000269|PubMed:16532395,
CC       ECO:0000269|PubMed:16917906}.
CC   -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC   -!- CAUTION: The sequence shown in this entry differs from the translation
CC       of the reference genome assembly (GRCh38/hg38) due to a nonsense
CC       variant creating stop codon at position 125 in the reference genome.
CC       {ECO:0000305}.
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DR   EMBL; AF464191; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF464192; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF464193; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF464194; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF464195; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF486844; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF486845; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF486846; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AF486847; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AY358222; AAQ88589.1; -; mRNA.
DR   EMBL; AP002004; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   RefSeq; NP_001177945.2; NM_001191016.2. [Q6UXS9-1]
DR   AlphaFoldDB; Q6UXS9; -.
DR   SMR; Q6UXS9; -.
DR   BioGRID; 125680; 16.
DR   IntAct; Q6UXS9; 5.
DR   BindingDB; Q6UXS9; -.
DR   ChEMBL; CHEMBL3831289; -.
DR   MEROPS; C14.P01; -.
DR   iPTMnet; Q6UXS9; -.
DR   PhosphoSitePlus; Q6UXS9; -.
DR   BioMuta; CASP12; -.
DR   DMDM; 395398427; -.
DR   jPOST; Q6UXS9; -.
DR   PeptideAtlas; Q6UXS9; -.
DR   ProteomicsDB; 67653; -. [Q6UXS9-1]
DR   ProteomicsDB; 67654; -. [Q6UXS9-2]
DR   ProteomicsDB; 67655; -. [Q6UXS9-3]
DR   DNASU; 100506742; -.
DR   Ensembl; ENST00000417998.5; ENSP00000424963.1; ENSG00000204403.11. [Q6UXS9-2]
DR   Ensembl; ENST00000458137.5; ENSP00000421408.1; ENSG00000204403.11. [Q6UXS9-2]
DR   Ensembl; ENST00000709446.1; ENSP00000517698.1; ENSG00000291983.1. [Q6UXS9-1]
DR   Ensembl; ENST00000709447.1; ENSP00000517699.1; ENSG00000291983.1. [Q6UXS9-6]
DR   Ensembl; ENST00000709448.1; ENSP00000517700.1; ENSG00000291983.1. [Q6UXS9-1]
DR   Ensembl; ENST00000709449.1; ENSP00000517701.1; ENSG00000291983.1. [Q6UXS9-2]
DR   Ensembl; ENST00000709450.1; ENSP00000517702.1; ENSG00000291983.1. [Q6UXS9-3]
DR   Ensembl; ENST00000709451.1; ENSP00000517703.1; ENSG00000291983.1. [Q6UXS9-5]
DR   Ensembl; ENST00000709452.1; ENSP00000517704.1; ENSG00000291983.1. [Q6UXS9-4]
DR   Ensembl; ENST00000709453.1; ENSP00000517705.1; ENSG00000291983.1. [Q6UXS9-8]
DR   Ensembl; ENST00000709454.1; ENSP00000517706.1; ENSG00000291983.1. [Q6UXS9-6]
DR   Ensembl; ENST00000709455.1; ENSP00000517707.1; ENSG00000291983.1. [Q6UXS9-2]
DR   Ensembl; ENST00000709456.1; ENSP00000517708.1; ENSG00000291983.1. [Q6UXS9-7]
DR   GeneID; 100506742; -.
DR   KEGG; hsa:100506742; -.
DR   MANE-Select; ENST00000709446.2; ENSP00000517698.1; NM_001191016.3; NP_001177945.2.
DR   UCSC; uc031qdp.3; human. [Q6UXS9-1]
DR   AGR; HGNC:19004; -.
DR   CTD; 100506742; -.
DR   DisGeNET; 100506742; -.
DR   GeneCards; CASP12; -.
DR   HGNC; HGNC:19004; CASP12.
DR   MIM; 608633; gene.
DR   neXtProt; NX_Q6UXS9; -.
DR   OpenTargets; ENSG00000204403; -.
DR   VEuPathDB; HostDB:ENSG00000204403; -.
DR   GeneTree; ENSGT00940000162555; -.
DR   HOGENOM; CLU_1585906_0_0_1; -.
DR   InParanoid; Q6UXS9; -.
DR   PhylomeDB; Q6UXS9; -.
DR   TreeFam; TF102023; -.
DR   BioCyc; MetaCyc:G66-33181-MONOMER; -.
DR   BRENDA; 3.4.22.B66; 2681.
DR   PathwayCommons; Q6UXS9; -.
DR   SignaLink; Q6UXS9; -.
DR   SIGNOR; Q6UXS9; -.
DR   BioGRID-ORCS; 100506742; 10 hits in 683 CRISPR screens.
DR   ChiTaRS; CASP12; human.
DR   GenomeRNAi; 100506742; -.
DR   Pharos; Q6UXS9; Tbio.
DR   PRO; PR:Q6UXS9; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q6UXS9; Protein.
DR   Bgee; ENSG00000204403; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 94 other cell types or tissues.
DR   ExpressionAtlas; Q6UXS9; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IEA:InterPro.
DR   GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR   CDD; cd08325; CARD_CASP1-like; 1.
DR   CDD; cd00032; CASc; 1.
DR   Gene3D; 3.40.50.1460; -; 1.
DR   Gene3D; 3.30.70.1470; Caspase-like; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR   InterPro; IPR001315; CARD.
DR   InterPro; IPR029030; Caspase-like_dom_sf.
DR   InterPro; IPR033139; Caspase_cys_AS.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR011600; Pept_C14_caspase.
DR   InterPro; IPR002138; Pept_C14_p10.
DR   InterPro; IPR001309; Pept_C14_p20.
DR   InterPro; IPR015917; Pept_C14A.
DR   PANTHER; PTHR47901; CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 18; 1.
DR   PANTHER; PTHR47901:SF6; CASPASE-12; 1.
DR   Pfam; PF00619; CARD; 1.
DR   Pfam; PF00656; Peptidase_C14; 1.
DR   PIRSF; PIRSF038001; Caspase_ICE; 1.
DR   PRINTS; PR00376; IL1BCENZYME.
DR   SMART; SM00115; CASc; 1.
DR   SUPFAM; SSF52129; Caspase-like; 1.
DR   SUPFAM; SSF47986; DEATH domain; 1.
DR   PROSITE; PS50209; CARD; 1.
DR   PROSITE; PS01122; CASPASE_CYS; 1.
DR   PROSITE; PS50207; CASPASE_P10; 1.
DR   PROSITE; PS50208; CASPASE_P20; 1.
DR   Genevisible; Q6UXS9; HS.
PE   2: Evidence at transcript level;
KW   Alternative splicing; Phosphoprotein; Reference proteome.
FT   CHAIN           1..341
FT                   /note="Inactive caspase-12"
FT                   /id="PRO_0000317441"
FT   DOMAIN          1..92
FT                   /note="CARD"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT   ACT_SITE        172
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        220
FT                   /evidence="ECO:0000255"
FT   MOD_RES         85
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q920D5"
FT   MOD_RES         90
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q920D5"
FT   VAR_SEQ         3..86
FT                   /note="Missing (in isoform 3 and isoform 8)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_061925"
FT   VAR_SEQ         87..168
FT                   /note="DISSDGEREANMPGLNIRNKEFNYLHNRNGSELDLLGMRDLLENLGYSVVIK
FT                   ENLTAQEMETALRQFAAHPEHQSSDSTFLV -> AFLEIQGAQPSGKLKLCPHAHFHEL
FT                   KTKRADEIYPVMEKERRTCLASTSATKNSTIFIIEMVLNLTFWGCEIYLKTLDTQWL
FT                   (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_030954"
FT   VAR_SEQ         145..341
FT                   /note="EMETALRQFAAHPEHQSSDSTFLVFMSHSILNGICGTKHWDQEPDVLHDDTI
FT                   FEIFNNRNCQSLKDKPKVIIMQACRGNGAGIVWFTTDSGKASADTHGRLLQGNICNDAV
FT                   TKAHVEKDFIAFKSSTPHNVSWRHETNGSVFISQIIYYFREYSWSHHLEEIFQKVQHSF
FT                   ETPNILTQLPTIERLSMTRYFYLFPGN -> MVLGLFGSPLTVEKPVQILMVGSCKVTS
FT                   VMMLLQRLMWKRTSLLSNLPHHIMFLGDMKQMALSSFPKLSTTSESILGVII (in
FT                   isoform 6 and isoform 8)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_061926"
FT   VAR_SEQ         145..309
FT                   /note="EMETALRQFAAHPEHQSSDSTFLVFMSHSILNGICGTKHWDQEPDVLHDDTI
FT                   FEIFNNRNCQSLKDKPKVIIMQACRGNGAGIVWFTTDSGKASADTHGRLLQGNICNDAV
FT                   TKAHVEKDFIAFKSSTPHNVSWRHETNGSVFISQIIYYFREYSWSHHLEEIFQK -> M
FT                   VLGLFGSPLTVEKPVQILMVGSCKVTSVMMLLQRLMWKRTSLLSNLPHH (in
FT                   isoform 3 and isoform 7)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_061927"
FT   VAR_SEQ         169..341
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_030955"
FT   VAR_SEQ         214..309
FT                   /note="VIIMQACRGNGAGIVWFTTDSGKASADTHGRLLQGNICNDAVTKAHVEKDFI
FT                   AFKSSTPHNVSWRHETNGSVFISQIIYYFREYSWSHHLEEIFQK -> MVLGLFGSPLT
FT                   VEKPVQILMVGSCKVTSVMMLLQRLMWKRTSLLSNLPHH (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_061928"
FT   VAR_SEQ         273..341
FT                   /note="HNVSWRHETNGSVFISQIIYYFREYSWSHHLEEIFQKVQHSFETPNILTQLP
FT                   TIERLSMTRYFYLFPGN -> RSTFI (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:12054529"
FT                   /id="VSP_061929"
FT   VARIANT         68
FT                   /note="I -> T (in dbSNP:rs693001)"
FT                   /id="VAR_080638"
FT   VARIANT         125..341
FT                   /note="Missing (in dbSNP:rs497116)"
FT                   /evidence="ECO:0000269|PubMed:12054529,
FT                   ECO:0000269|PubMed:15129283, ECO:0000269|PubMed:16532395,
FT                   ECO:0000269|PubMed:16554811, ECO:0000269|PubMed:16917906"
FT                   /id="VAR_080639"
FT   VARIANT         238
FT                   /note="S -> G (in dbSNP:rs647039)"
FT                   /id="VAR_080640"
FT   CONFLICT        Q6UXS9-2:88
FT                   /note="F -> L (in Ref. 1; AF486844/AF486845)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   341 AA;  38907 MW;  5D7DFAA40D91B18A CRC64;
     MADEKPSNGV LVHMVKLLIK TFLDGIFDDL MENNVLNTDE IHLIGKCLKF VVSNAENLVD
     DITETAQIAG KIFREHLWNS KKQLSSDISS DGEREANMPG LNIRNKEFNY LHNRNGSELD
     LLGMRDLLEN LGYSVVIKEN LTAQEMETAL RQFAAHPEHQ SSDSTFLVFM SHSILNGICG
     TKHWDQEPDV LHDDTIFEIF NNRNCQSLKD KPKVIIMQAC RGNGAGIVWF TTDSGKASAD
     THGRLLQGNI CNDAVTKAHV EKDFIAFKSS TPHNVSWRHE TNGSVFISQI IYYFREYSWS
     HHLEEIFQKV QHSFETPNIL TQLPTIERLS MTRYFYLFPG N
//