ID   HYAL3_HUMAN             Reviewed;         417 AA.
AC   O43820; O60540; Q8NFK2; Q8NFK3; Q8NFK4; Q96E56; Q9BRW9;
DT   05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-1998, sequence version 1.
DT   27-MAR-2024, entry version 176.
DE   RecName: Full=Hyaluronidase-3;
DE            Short=Hyal-3;
DE            EC=3.2.1.35 {ECO:0000269|PubMed:12084718};
DE   AltName: Full=Hyaluronoglucosaminidase-3;
DE   AltName: Full=Lung carcinoma protein 3;
DE            Short=LuCa-3;
DE   Flags: Precursor;
GN   Name=HYAL3; Synonyms=LUCA3;
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] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX   PubMed=10493834; DOI=10.1006/geno.1999.5876;
RA   Csoka A.B., Scherer S.W., Stern R.;
RT   "Expression analysis of six paralogous human hyaluronidase genes clustered
RT   on chromosomes 3p21 and 7q31.";
RL   Genomics 60:356-361(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), CATALYTIC ACTIVITY,
RP   AND ALTERNATIVE SPLICING.
RX   PubMed=12084718; DOI=10.1074/jbc.m203821200;
RA   Lokeshwar V.B., Schroeder G.L., Carey R.I., Soloway M.S., Iida N.;
RT   "Regulation of hyaluronidase activity by alternative mRNA splicing.";
RL   J. Biol. Chem. 277:33654-33663(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Fong K., Bader S., Lee C.-C., Latif F., Sekido Y., Duh F.-M., Wei M.-H.,
RA   Cundiff S., Lerman M.I., Minna J.D.;
RT   "LUCA-3 a third hyaluronidase gene and candidate tumor suppressor gene
RT   located in the 3p21.3 homozygous deletion region.";
RL   Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16641997; DOI=10.1038/nature04728;
RA   Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA   Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA   Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA   Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA   Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA   Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA   Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA   Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA   Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA   Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA   Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA   Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA   Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA   Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA   Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA   Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA   Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA   Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA   Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT   "The DNA sequence, annotation and analysis of human chromosome 3.";
RL   Nature 440:1194-1198(2006).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT TYR-113.
RC   TISSUE=Bone marrow, and Ovary;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   TISSUE SPECIFICITY.
RX   PubMed=20586096; DOI=10.1002/mrd.21217;
RA   Reese K.L., Aravindan R.G., Griffiths G.S., Shao M., Wang Y., Galileo D.S.,
RA   Atmuri V., Triggs-Raine B.L., Martin-Deleon P.A.;
RT   "Acidic hyaluronidase activity is present in mouse sperm and is reduced in
RT   the absence of SPAM1: evidence for a role for hyaluronidase 3 in mouse and
RT   human sperm.";
RL   Mol. Reprod. Dev. 77:759-772(2010).
RN   [7]
RP   TISSUE SPECIFICITY, AND INDUCTION.
RX   PubMed=21699545; DOI=10.1111/j.1751-1097.2011.00959.x;
RA   Kurdykowski S., Mine S., Bardey V., Danoux L., Jeanmaire C., Pauly G.,
RA   Brabencova E., Wegrowski Y., Maquart F.X.;
RT   "Ultraviolet-B irradiation induces differential regulations of
RT   hyaluronidase expression and activity in normal human keratinocytes.";
RL   Photochem. Photobiol. 87:1105-1112(2011).
CC   -!- FUNCTION: Facilitates sperm penetration into the layer of cumulus cells
CC       surrounding the egg by digesting hyaluronic acid. Involved in induction
CC       of the acrosome reaction in the sperm. Involved in follicular atresia,
CC       the breakdown of immature ovarian follicles that are not selected to
CC       ovulate. Induces ovarian granulosa cell apoptosis, possibly via
CC       apoptotic signaling pathway involving CASP8 and CASP3 activation, and
CC       poly(ADP-ribose) polymerase (PARP) cleavage. Has no hyaluronidase
CC       activity in embryonic fibroblasts in vitro. Has no hyaluronidase
CC       activity in granulosa cells in vitro. {ECO:0000250|UniProtKB:Q8VEI3}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Random hydrolysis of (1->4)-linkages between N-acetyl-beta-D-
CC         glucosamine and D-glucuronate residues in hyaluronate.; EC=3.2.1.35;
CC         Evidence={ECO:0000269|PubMed:12084718};
CC   -!- INTERACTION:
CC       O43820; Q8N9W6-4: BOLL; NbExp=3; IntAct=EBI-3913399, EBI-11983447;
CC       O43820; Q9UQM7: CAMK2A; NbExp=3; IntAct=EBI-3913399, EBI-1383687;
CC       O43820; O75553: DAB1; NbExp=3; IntAct=EBI-3913399, EBI-7875264;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q8VEI3}. Cell
CC       membrane {ECO:0000250|UniProtKB:Q8VEI3}. Cytoplasmic vesicle, secretory
CC       vesicle, acrosome {ECO:0000250|UniProtKB:Q8VEI3}. Endoplasmic reticulum
CC       {ECO:0000250|UniProtKB:Q8VEI3}. Early endosome
CC       {ECO:0000250|UniProtKB:Q8VEI3}. Note=Mostly present in low-density
CC       vesicles. Low levels in higher density vesicles of late endosomes and
CC       lysosomes. Localized in punctate cytoplasmic vesicles and in
CC       perinuclear structures, but does not colocalize with LAMP1. Localized
CC       on the plasma membrane over the acrosome and on the surface of the
CC       midpiece of the sperm tail. {ECO:0000250|UniProtKB:Q8VEI3}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=1;
CC         IsoId=O43820-1; Sequence=Displayed;
CC       Name=2; Synonyms=HYAL3v1;
CC         IsoId=O43820-2; Sequence=VSP_020194;
CC       Name=3; Synonyms=HYAL3v2;
CC         IsoId=O43820-3; Sequence=VSP_020192, VSP_020193;
CC       Name=4; Synonyms=HYAL3v3;
CC         IsoId=O43820-4; Sequence=VSP_020192, VSP_020193, VSP_020194;
CC   -!- TISSUE SPECIFICITY: Expressed in sperm (PubMed:20586096). Highly
CC       expressed in epidermis of the skin, where it is expressed
CC       intracellularily in the deep horny layer (at protein level)
CC       (PubMed:21699545). Bone marrow, testis and kidney (PubMed:10493834).
CC       {ECO:0000269|PubMed:10493834, ECO:0000269|PubMed:20586096,
CC       ECO:0000269|PubMed:21699545}.
CC   -!- INDUCTION: Expression is not significantly up- or down-regulated by
CC       ultraviolet irradiation B (UV-B) in epidermis (PubMed:21699545).
CC       {ECO:0000269|PubMed:21699545}.
CC   -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8VEI3}.
CC   -!- MISCELLANEOUS: [Isoform 2]: Enzymatically inactive. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform 3]: Enzymatically inactive. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform 4]: Enzymatically inactive. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 56 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAC70915.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; AF036035; AAD04257.1; -; mRNA.
DR   EMBL; AF502909; AAM60775.1; -; mRNA.
DR   EMBL; AF502910; AAM60776.1; -; mRNA.
DR   EMBL; AF502911; AAM60777.1; -; mRNA.
DR   EMBL; AF502912; AAM60778.1; -; mRNA.
DR   EMBL; AF040710; AAC70915.1; ALT_FRAME; mRNA.
DR   EMBL; U73167; AAC02729.1; -; Genomic_DNA.
DR   EMBL; BC005896; AAH05896.1; -; mRNA.
DR   EMBL; BC012892; AAH12892.1; -; mRNA.
DR   CCDS; CCDS2815.1; -. [O43820-1]
DR   CCDS; CCDS56257.1; -. [O43820-2]
DR   CCDS; CCDS56259.1; -. [O43820-4]
DR   CCDS; CCDS56260.1; -. [O43820-3]
DR   RefSeq; NP_001186958.1; NM_001200029.1. [O43820-1]
DR   RefSeq; NP_001186959.1; NM_001200030.1. [O43820-2]
DR   RefSeq; NP_001186960.1; NM_001200031.1. [O43820-3]
DR   RefSeq; NP_001186961.1; NM_001200032.1. [O43820-4]
DR   RefSeq; NP_003540.2; NM_003549.3. [O43820-1]
DR   AlphaFoldDB; O43820; -.
DR   SMR; O43820; -.
DR   BioGRID; 113967; 13.
DR   IntAct; O43820; 6.
DR   STRING; 9606.ENSP00000337425; -.
DR   DrugBank; DB08818; Hyaluronic acid.
DR   CAZy; GH56; Glycoside Hydrolase Family 56.
DR   GlyCosmos; O43820; 2 sites, No reported glycans.
DR   GlyGen; O43820; 2 sites.
DR   BioMuta; HYAL3; -.
DR   EPD; O43820; -.
DR   MassIVE; O43820; -.
DR   PaxDb; 9606-ENSP00000337425; -.
DR   PeptideAtlas; O43820; -.
DR   ProteomicsDB; 49183; -. [O43820-1]
DR   ProteomicsDB; 49184; -. [O43820-2]
DR   ProteomicsDB; 49185; -. [O43820-3]
DR   ProteomicsDB; 49186; -. [O43820-4]
DR   Antibodypedia; 34877; 238 antibodies from 27 providers.
DR   DNASU; 8372; -.
DR   Ensembl; ENST00000336307.6; ENSP00000337425.1; ENSG00000186792.17. [O43820-1]
DR   Ensembl; ENST00000359051.7; ENSP00000351946.3; ENSG00000186792.17. [O43820-2]
DR   Ensembl; ENST00000415204.5; ENSP00000401092.1; ENSG00000186792.17. [O43820-3]
DR   Ensembl; ENST00000450982.6; ENSP00000391922.1; ENSG00000186792.17. [O43820-2]
DR   Ensembl; ENST00000513170.1; ENSP00000424633.1; ENSG00000186792.17. [O43820-4]
DR   Ensembl; ENST00000621157.5; ENSP00000479935.1; ENSG00000186792.17. [O43820-1]
DR   GeneID; 8372; -.
DR   KEGG; hsa:8372; -.
DR   MANE-Select; ENST00000336307.6; ENSP00000337425.1; NM_003549.4; NP_003540.2.
DR   UCSC; uc003czd.3; human. [O43820-1]
DR   AGR; HGNC:5322; -.
DR   CTD; 8372; -.
DR   DisGeNET; 8372; -.
DR   GeneCards; HYAL3; -.
DR   HGNC; HGNC:5322; HYAL3.
DR   HPA; ENSG00000186792; Tissue enhanced (bone).
DR   MIM; 604038; gene.
DR   neXtProt; NX_O43820; -.
DR   OpenTargets; ENSG00000186792; -.
DR   PharmGKB; PA29573; -.
DR   VEuPathDB; HostDB:ENSG00000186792; -.
DR   eggNOG; ENOG502QTXP; Eukaryota.
DR   GeneTree; ENSGT01020000230364; -.
DR   HOGENOM; CLU_036366_0_0_1; -.
DR   InParanoid; O43820; -.
DR   OMA; GWATSWH; -.
DR   OrthoDB; 5344684at2759; -.
DR   PhylomeDB; O43820; -.
DR   TreeFam; TF321598; -.
DR   BioCyc; MetaCyc:ENSG00000114366-MONOMER; -.
DR   BRENDA; 3.2.1.35; 2681.
DR   PathwayCommons; O43820; -.
DR   Reactome; R-HSA-2024101; CS/DS degradation.
DR   Reactome; R-HSA-2160916; Hyaluronan uptake and degradation.
DR   SignaLink; O43820; -.
DR   BioGRID-ORCS; 8372; 20 hits in 1152 CRISPR screens.
DR   ChiTaRS; HYAL3; human.
DR   GeneWiki; HYAL3; -.
DR   GenomeRNAi; 8372; -.
DR   Pharos; O43820; Tbio.
DR   PRO; PR:O43820; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; O43820; Protein.
DR   Bgee; ENSG00000186792; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 97 other cell types or tissues.
DR   ExpressionAtlas; O43820; baseline and differential.
DR   GO; GO:0002080; C:acrosomal membrane; ISS:UniProtKB.
DR   GO; GO:0001669; C:acrosomal vesicle; ISS:UniProtKB.
DR   GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR   GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0097225; C:sperm midpiece; ISS:UniProtKB.
DR   GO; GO:0033906; F:hyaluronoglucuronidase activity; IDA:UniProtKB.
DR   GO; GO:0004415; F:hyalurononglucosaminidase activity; IDA:UniProtKB.
DR   GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro.
DR   GO; GO:0051216; P:cartilage development; IEP:UniProtKB.
DR   GO; GO:0071347; P:cellular response to interleukin-1; IDA:UniProtKB.
DR   GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:UniProtKB.
DR   GO; GO:0071493; P:cellular response to UV-B; IDA:UniProtKB.
DR   GO; GO:0030214; P:hyaluronan catabolic process; IDA:UniProtKB.
DR   GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR   GO; GO:2000355; P:negative regulation of ovarian follicle development; ISS:UniProtKB.
DR   GO; GO:0001552; P:ovarian follicle atresia; ISS:UniProtKB.
DR   GO; GO:0007341; P:penetration of zona pellucida; ISS:UniProtKB.
DR   GO; GO:2000368; P:positive regulation of acrosomal vesicle exocytosis; ISS:UniProtKB.
DR   GO; GO:0046677; P:response to antibiotic; IEP:UniProtKB.
DR   GO; GO:0009615; P:response to virus; IDA:UniProtKB.
DR   Gene3D; 3.20.20.70; Aldolase class I; 1.
DR   InterPro; IPR013785; Aldolase_TIM.
DR   InterPro; IPR017853; Glycoside_hydrolase_SF.
DR   InterPro; IPR018155; Hyaluronidase.
DR   InterPro; IPR027260; Hyaluronidase-3.
DR   PANTHER; PTHR11769; HYALURONIDASE; 1.
DR   PANTHER; PTHR11769:SF19; HYALURONIDASE-3; 1.
DR   Pfam; PF01630; Glyco_hydro_56; 1.
DR   PIRSF; PIRSF038193; Hyaluronidase; 1.
DR   PIRSF; PIRSF500776; Hyaluronidase_3; 1.
DR   PRINTS; PR00846; GLHYDRLASE56.
DR   SUPFAM; SSF51445; (Trans)glycosidases; 1.
DR   PROSITE; PS00022; EGF_1; 1.
DR   PROSITE; PS01186; EGF_2; 1.
DR   Genevisible; O43820; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell membrane; Cytoplasmic vesicle; Disulfide bond;
KW   EGF-like domain; Endoplasmic reticulum; Endosome; Fertilization;
KW   Glycoprotein; Glycosidase; Hydrolase; Membrane; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..20
FT                   /evidence="ECO:0000255"
FT   CHAIN           21..417
FT                   /note="Hyaluronidase-3"
FT                   /id="PRO_0000248200"
FT   DOMAIN          352..407
FT                   /note="EGF-like"
FT   ACT_SITE        129
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   CARBOHYD        69
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        215
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        42..331
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   DISULFID        205..220
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   DISULFID        356..367
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   DISULFID        361..395
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   DISULFID        397..406
FT                   /evidence="ECO:0000250|UniProtKB:Q12794"
FT   VAR_SEQ         1..249
FT                   /note="Missing (in isoform 3 and isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:12084718"
FT                   /id="VSP_020192"
FT   VAR_SEQ         250
FT                   /note="R -> M (in isoform 3 and isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:12084718"
FT                   /id="VSP_020193"
FT   VAR_SEQ         299..328
FT                   /note="Missing (in isoform 2 and isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:12084718"
FT                   /id="VSP_020194"
FT   VARIANT         113
FT                   /note="H -> Y (in dbSNP:rs13100173)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_027263"
FT   CONFLICT        54
FT                   /note="A -> S (in Ref. 5; AAH05896)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   417 AA;  46501 MW;  A6E7DE5369EF2BB8 CRC64;
     MTTQLGPALV LGVALCLGCG QPLPQVPERP FSVLWNVPSA HCEARFGVHL PLNALGIIAN
     RGQHFHGQNM TIFYKNQLGL YPYFGPRGTA HNGGIPQALP LDRHLALAAY QIHHSLRPGF
     AGPAVLDWEE WCPLWAGNWG RRRAYQAASW AWAQQVFPDL DPQEQLYKAY TGFEQAARAL
     MEDTLRVAQA LRPHGLWGFY HYPACGNGWH SMASNYTGRC HAATLARNTQ LHWLWAASSA
     LFPSIYLPPR LPPAHHQAFV RHRLEEAFRV ALVGHRHPLP VLAYVRLTHR RSGRFLSQDD
     LVQSIGVSAA LGAAGVVLWG DLSLSSSEEE CWHLHDYLVD TLGPYVINVT RAAMACSHQR
     CHGHGRCARR DPGQMEAFLH LWPDGSLGDW KSFSCHCYWG WAGPTCQEPR PGPKEAV
//