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UniProtKB - P40818 (UBP8_HUMAN)

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Protein

Ubiquitin carboxyl-terminal hydrolase 8

Gene

USP8

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

Functioni

Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1.4 Publications

Catalytic activityi

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei786NucleophilePROSITE-ProRule annotation1
Active sitei1067Proton acceptorPROSITE-ProRule annotation1

GO - Molecular functioni

  • cadherin binding Source: BHF-UCL
  • cysteine-type endopeptidase activity Source: ProtInc
  • SH3 domain binding Source: UniProtKB-KW
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
View the complete GO annotation on QuickGO ...

GO - Biological processi

  • cell proliferation Source: ProtInc
  • cellular response to dexamethasone stimulus Source: Ensembl
  • cellular response to nerve growth factor stimulus Source: Ensembl
  • endosome organization Source: UniProtKB
  • mitotic cytokinesis Source: MGI
  • positive regulation of canonical Wnt signaling pathway Source: FlyBase
  • protein deubiquitination Source: MGI
  • protein K48-linked deubiquitination Source: UniProtKB
  • protein K63-linked deubiquitination Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: InterPro
View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processCell cycle, Ubl conjugation pathway

Enzyme and pathway databases

BRENDAi3.4.19.12 2681
ReactomeiR-HSA-1358803 Downregulation of ERBB2:ERBB3 signaling
R-HSA-4641263 Regulation of FZD by ubiquitination
R-HSA-5689880 Ub-specific processing proteases
R-HSA-6807004 Negative regulation of MET activity
SignaLinkiP40818

Protein family/group databases

MEROPSiC19.011

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 8 (EC:3.4.19.121 Publication)
Alternative name(s):
Deubiquitinating enzyme 8
Ubiquitin isopeptidase Y
Short name:
hUBPy
Ubiquitin thioesterase 8
Ubiquitin-specific-processing protease 8
Gene namesi
Name:USP8
Synonyms:KIAA0055, UBPY
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

EuPathDBiHostDB:ENSG00000138592.13
HGNCiHGNC:12631 USP8
MIMi603158 gene
neXtProtiNX_P40818

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

Cell membrane, Cytoplasm, Endosome, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Pituitary adenoma 4, ACTH-secreting (PITA4)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes.
See also OMIM:219090
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_079717718 – 723Missing in PITA4; somatic mutation; unknown pathological significance. 1 Publication6
Natural variantiVAR_079718718S → C in PITA4; somatic mutation; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs672601308EnsemblClinVar.1
Natural variantiVAR_079719718S → P in PITA4; somatic mutation; unknown pathological significance; localizes to nucleus instead of cytoplasm. 1 PublicationCorresponds to variant dbSNP:rs672601307EnsemblClinVar.1
Natural variantiVAR_079720718Missing in PITA4; somatic mutation; unknown pathological significance. 1 Publication1
Natural variantiVAR_079721720P → R in PITA4; somatic mutation; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs672601311EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi786C → S: Impairs deubiquitination activity and leads to endosome membrane accumulation. 1 Publication1

Keywords - Diseasei

Cushing syndrome, Disease mutation

Organism-specific databases

DisGeNETi9101
MalaCardsiUSP8
MIMi219090 phenotype
OpenTargetsiENSG00000138592
Orphaneti401795 Autosomal recessive spastic paraplegia type 59
PharmGKBiPA37256

Chemistry databases

ChEMBLiCHEMBL2157854

Polymorphism and mutation databases

BioMutaiUSP8
DMDMi731046

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000806271 – 1118Ubiquitin carboxyl-terminal hydrolase 8Add BLAST1118

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei160PhosphoserineCombined sources1
Modified residuei392PhosphoserineCombined sources1
Modified residuei400PhosphoserineCombined sources1
Modified residuei452PhosphoserineCombined sources1
Modified residuei577PhosphothreonineCombined sources1
Modified residuei718PhosphoserineCombined sources1
Modified residuei719PhosphoserineCombined sources1
Modified residuei945PhosphothreonineBy similarity1

Post-translational modificationi

Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR-dependent manner.By similarity
Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF-stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP40818
MaxQBiP40818
PaxDbiP40818
PeptideAtlasiP40818
PRIDEiP40818
ProteomicsDBi55380

PTM databases

iPTMnetiP40818
PhosphoSitePlusiP40818

Expressioni

Inductioni

Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact.1 Publication

Gene expression databases

BgeeiENSG00000138592
CleanExiHS_USP8
ExpressionAtlasiP40818 baseline and differential
GenevisibleiP40818 HS

Organism-specific databases

HPAiHPA050215

Interactioni

Subunit structurei

Forms a ternary complex with RNF128 and OTUB1. Interacts (via C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1, RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1, RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with microtubules (By similarity). Interacts with BIRC6/bruce and KIF23/MKLP1.By similarity5 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi114555, 83 interactors
DIPiDIP-40365N
IntActiP40818, 31 interactors
MINTiP40818
STRINGi9606.ENSP00000302239

Chemistry databases

BindingDBiP40818

Structurei

Secondary structure

11118
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi17 – 21Combined sources5
Helixi22 – 24Combined sources3
Helixi28 – 30Combined sources3
Helixi33 – 52Combined sources20
Helixi56 – 73Combined sources18
Helixi77 – 81Combined sources5
Helixi83 – 90Combined sources8
Helixi92 – 138Combined sources47
Beta strandi181 – 183Combined sources3
Helixi185 – 193Combined sources9
Beta strandi195 – 197Combined sources3
Beta strandi199 – 203Combined sources5
Helixi207 – 212Combined sources6
Beta strandi219 – 221Combined sources3
Helixi223 – 225Combined sources3
Helixi232 – 237Combined sources6
Helixi241 – 248Combined sources8
Turni249 – 252Combined sources4
Beta strandi253 – 259Combined sources7
Helixi265 – 267Combined sources3
Helixi273 – 282Combined sources10
Beta strandi295 – 297Combined sources3
Helixi300 – 307Combined sources8
Helixi309 – 311Combined sources3
Helixi763 – 765Combined sources3
Beta strandi782 – 784Combined sources3
Helixi786 – 796Combined sources11
Helixi799 – 806Combined sources8
Turni807 – 809Combined sources3
Helixi810 – 813Combined sources4
Helixi825 – 839Combined sources15
Beta strandi842 – 845Combined sources4
Helixi848 – 857Combined sources10
Helixi859 – 861Combined sources3
Beta strandi862 – 865Combined sources4
Helixi869 – 884Combined sources16
Helixi903 – 917Combined sources15
Helixi921 – 926Combined sources6
Beta strandi928 – 936Combined sources9
Turni937 – 939Combined sources3
Beta strandi942 – 954Combined sources13
Beta strandi959 – 963Combined sources5
Helixi964 – 971Combined sources8
Beta strandi975 – 977Combined sources3
Helixi979 – 981Combined sources3
Beta strandi983 – 985Combined sources3
Turni986 – 989Combined sources4
Beta strandi990 – 992Combined sources3
Beta strandi994 – 1002Combined sources9
Beta strandi1005 – 1011Combined sources7
Beta strandi1014 – 1016Combined sources3
Beta strandi1018 – 1023Combined sources6
Beta strandi1027 – 1029Combined sources3
Helixi1038 – 1040Combined sources3
Beta strandi1051 – 1061Combined sources11
Turni1063 – 1065Combined sources3
Beta strandi1067 – 1074Combined sources8
Turni1075 – 1078Combined sources4
Beta strandi1079 – 1084Combined sources6
Beta strandi1087 – 1090Combined sources4
Helixi1093 – 1095Combined sources3
Beta strandi1101 – 1107Combined sources7

3D structure databases

ProteinModelPortaliP40818
SMRiP40818
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP40818

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini33 – 116MITAdd BLAST84
Domaini195 – 313RhodanesePROSITE-ProRule annotationAdd BLAST119
Domaini777 – 1109USPAdd BLAST333

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi405 – 413SH3-bindingBy similarity9

Domaini

The MIT domain is required for endosomal localization, CHMP1B-binding, maintenance of ESCRT-0 stability and EGFR degradation.1 Publication
The rhodanese domain is sufficient for RNF41-binding.By similarity

Sequence similaritiesi

Belongs to the peptidase C19 family.Curated

Keywords - Domaini

SH3-binding

Phylogenomic databases

eggNOGiKOG1868 Eukaryota
ENOG410XP8T LUCA
GeneTreeiENSGT00860000133682
HOGENOMiHOG000231497
HOVERGENiHBG012631
InParanoidiP40818
KOiK11839
OMAiVPQIDRT
OrthoDBiEOG091G0120
PhylomeDBiP40818
TreeFamiTF106277

Family and domain databases

Gene3Di3.40.250.10, 1 hit
InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001394 Peptidase_C19_UCH
IPR001763 Rhodanese-like_dom
IPR036873 Rhodanese-like_dom_sf
IPR015063 USP8_dimer
IPR018200 USP_CS
IPR028889 USP_dom
PfamiView protein in Pfam
PF00581 Rhodanese, 1 hit
PF00443 UCH, 1 hit
PF08969 USP8_dimer, 1 hit
SUPFAMiSSF52821 SSF52821, 1 hit
SSF54001 SSF54001, 1 hit
PROSITEiView protein in PROSITE
PS50206 RHODANESE_3, 1 hit
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P40818-1) [UniParc]FASTAAdd to basket

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
MPAVASVPKE LYLSSSLKDL NKKTEVKPEK ISTKSYVHSA LKIFKTAEEC 
        60         70         80         90        100
RLDRDEERAY VLYMKYVTVY NLIKKRPDFK QQQDYFHSIL GPGNIKKAVE 
       110        120        130        140        150
EAERLSESLK LRYEEAEVRK KLEEKDRQEE AQRLQQKRQE TGREDGGTLA 
       160        170        180        190        200
KGSLENVLDS KDKTQKSNGE KNEKCETKEK GAITAKELYT MMTDKNISLI 
       210        220        230        240        250
IMDARRMQDY QDSCILHSLS VPEEAISPGV TASWIEAHLP DDSKDTWKKR 
       260        270        280        290        300
GNVEYVVLLD WFSSAKDLQI GTTLRSLKDA LFKWESKTVL RNEPLVLEGG 
       310        320        330        340        350
YENWLLCYPQ YTTNAKVTPP PRRQNEEVSI SLDFTYPSLE ESIPSKPAAQ 
       360        370        380        390        400
TPPASIEVDE NIELISGQNE RMGPLNISTP VEPVAASKSD VSPIIQPVPS 
       410        420        430        440        450
IKNVPQIDRT KKPAVKLPEE HRIKSESTNH EQQSPQSGKV IPDRSTKPVV 
       460        470        480        490        500
FSPTLMLTDE EKARIHAETA LLMEKNKQEK ELRERQQEEQ KEKLRKEEQE 
       510        520        530        540        550
QKAKKKQEAE ENEITEKQQK AKEEMEKKES EQAKKEDKET SAKRGKEITG 
       560        570        580        590        600
VKRQSKSEHE TSDAKKSVED RGKRCPTPEI QKKSTGDVPH TSVTGDSGSG 
       610        620        630        640        650
KPFKIKGQPE SGILRTGTFR EDTDDTERNK AQREPLTRAR SEEMGRIVPG 
       660        670        680        690        700
LPSGWAKFLD PITGTFRYYH SPTNTVHMYP PEMAPSSAPP STPPTHKAKP 
       710        720        730        740        750
QIPAERDREP SKLKRSYSSP DITQAIQEEE KRKPTVTPTV NRENKPTCYP 
       760        770        780        790        800
KAEISRLSAS QIRNLNPVFG GSGPALTGLR NLGNTCYMNS ILQCLCNAPH 
       810        820        830        840        850
LADYFNRNCY QDDINRSNLL GHKGEVAEEF GIIMKALWTG QYRYISPKDF 
       860        870        880        890        900
KITIGKINDQ FAGYSQQDSQ ELLLFLMDGL HEDLNKADNR KRYKEENNDH 
       910        920        930        940        950
LDDFKAAEHA WQKHKQLNES IIVALFQGQF KSTVQCLTCH KKSRTFEAFM 
       960        970        980        990       1000
YLSLPLASTS KCTLQDCLRL FSKEEKLTDN NRFYCSHCRA RRDSLKKIEI 
      1010       1020       1030       1040       1050
WKLPPVLLVH LKRFSYDGRW KQKLQTSVDF PLENLDLSQY VIGPKNNLKK 
      1060       1070       1080       1090       1100
YNLFSVSNHY GGLDGGHYTA YCKNAARQRW FKFDDHEVSD ISVSSVKSSA 
      1110 
AYILFYTSLG PRVTDVAT
Length:1,118
Mass (Da):127,523
Last modified:February 1, 1995 - v1
Checksum:i8B884B7A842F9A9A
GO
Isoform 2 (identifier: P40818-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     35-111: Missing.
     601-629: Missing.

Note: No experimental confirmation available.
Show »
Length:1,012
Mass (Da):115,080
Checksum:iB31B38D37E837812
GO

Sequence cautioni

The sequence AAH38801 differs from that shown. Contaminating sequence. Potential poly-A sequence.Curated
The sequence AAH51345 differs from that shown. Contaminating sequence. Potential poly-A sequence.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti526E → G in CAD97662 (PubMed:17974005).Curated1
Sequence conflicti717Y → H in CAD97662 (PubMed:17974005).Curated1
Sequence conflicti945T → A in CAD97662 (PubMed:17974005).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_077850310Q → K Found in a patient with spastic paraplegia; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs587777201EnsemblClinVar.1
Natural variantiVAR_017796443D → G. Corresponds to variant dbSNP:rs3743044EnsemblClinVar.1
Natural variantiVAR_079717718 – 723Missing in PITA4; somatic mutation; unknown pathological significance. 1 Publication6
Natural variantiVAR_079718718S → C in PITA4; somatic mutation; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs672601308EnsemblClinVar.1
Natural variantiVAR_079719718S → P in PITA4; somatic mutation; unknown pathological significance; localizes to nucleus instead of cytoplasm. 1 PublicationCorresponds to variant dbSNP:rs672601307EnsemblClinVar.1
Natural variantiVAR_079720718Missing in PITA4; somatic mutation; unknown pathological significance. 1 Publication1
Natural variantiVAR_079721720P → R in PITA4; somatic mutation; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs672601311EnsemblClinVar.1
Natural variantiVAR_051525739T → A. Corresponds to variant dbSNP:rs11638390Ensembl.1
Natural variantiVAR_017797827A → G. Corresponds to variant dbSNP:rs1056577Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05459435 – 111Missing in isoform 2. 1 PublicationAdd BLAST77
Alternative sequenceiVSP_054595601 – 629Missing in isoform 2. 1 PublicationAdd BLAST29

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D29956 mRNA Translation: BAA06225.2
AK296480 mRNA Translation: BAG59120.1
BX537420 mRNA Translation: CAD97662.1
AC012170 Genomic DNA No translation available.
BC038801 mRNA Translation: AAH38801.1 Sequence problems.
BC051345 mRNA Translation: AAH51345.1 Sequence problems.
BC110590 mRNA Translation: AAI10591.1
CCDSiCCDS10137.1 [P40818-1]
CCDS61632.1 [P40818-2]
RefSeqiNP_001122082.1, NM_001128610.2 [P40818-1]
NP_001269978.1, NM_001283049.1 [P40818-2]
NP_005145.3, NM_005154.4 [P40818-1]
XP_006720824.1, XM_006720761.3 [P40818-1]
XP_011520495.1, XM_011522193.2 [P40818-1]
UniGeneiHs.443731

Genome annotation databases

EnsembliENST00000307179; ENSP00000302239; ENSG00000138592 [P40818-1]
ENST00000396444; ENSP00000379721; ENSG00000138592 [P40818-1]
ENST00000425032; ENSP00000412682; ENSG00000138592 [P40818-2]
GeneIDi9101
KEGGihsa:9101
UCSCiuc001zyl.6 human [P40818-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiUBP8_HUMAN
AccessioniPrimary (citable) accession number: P40818
Secondary accession number(s): B4DKA8
, Q2TB31, Q7Z3U2, Q86VA0, Q8IWI7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: July 18, 2018
This is version 199 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families

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