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FLASH GENE
Symbol USP8 contributors: mct/npt/pgu - updated : 28-04-2016
HGNC name ubiquitin specific protease 8
HGNC id 12631
DNA
TYPE functioning gene
STRUCTURE 76.70 kb     20 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status provisional
Physical map
LOC283652 MYEF2 15q15.1 myelin expression factor 2 SLC12A1 15q15-q21 solute carrier family 12 (sodium/potassium/chloride transporters), member 1 DUT 15q21.1 dUTP pyrophosphatase FBN1 15q21.1 fibrillin 1 (Marfan syndrome) LOC388119 15 similar to Oxr1 protein KIAA0912 15q15.3 KIAA0912 protein CRI1 15q21.1-q21.2 CREBBP/EP300 inhibitory protein 1 LOC390582 15 similar to keratin 8; cytokeratin 8; keratin, type II cytoskeletal 8 KIAA0256 15q15.3 KIAA0256 gene product TRIP15 15q21.2 KIAA0256 gene product LOC390583 15 similar to Protein C6orf66 (HSPC125) (My013 protein) GALK2 15q21.1 galactokinase 2 FLJ32800 15q15.3 hypothetical protein FLJ32800 LOC390584 15 similar to putative intramembrane cleaving protease; presenilin-like protein 2; intramembrane protease 3 FGF7 15q15-q21.1 fibroblast growth factor 7 (keratinocyte growth factor) MDS009 15q15.3 x 009 protein LOC388120 15 hypothetical gene supported by BC013357; NM_016120 ATP8B4 15q15.3 ATPase, Class I, type 8B, member 4 SLC27A2 15q21.2 solute carrier family 27 (fatty acid transporter), member 2 HDC 15q15-q21 histidine decarboxylase GABPB2 15q15.2 GA binding protein transcription factor, beta subunit 2, 47kDa FLJ10038 15q15.3 hypothetical protein FLJ10038 USP8 6p21.3 ubiquitin specific protease 8 TRPM7 15q21 transient receptor potential cation channel, subfamily M, member 7 SPPL2A 15q15.3 putative intramembrane cleaving protease AP4E1 15q15.2 adaptor-related protein complex 4, epsilon 1 subunit LOC388121 15 similar to TNF-induced protein CYP19A1 15q21.1 cytochrome P450, family 19, subfamily A, polypeptide 1 FLJ11181 15q15.3 hypothetical protein FLJ11181 CRG-L2 15q15.3 likely ortholog of mouse cancer related gene - liver 2 RC3 15q15.3 rabconnectin-3 SCG3 15q21 secretogranin III MGC35274 15q21.1 hypothetical protein MGC35274 TMOD2 15q21.1-q21.2 tropomodulin 2 (neuronal) TMOD3 15q21.1-q21.2 tropomodulin 3 (ubiquitous) LOC123169 15q21.1 senescence downregulated leo1-like MAPK6 15q21 mitogen-activated protein kinase 6 BCL2L10 15q21 BCL2-like 10 (apoptosis facilitator) GNB5 15q21 guanine nucleotide binding protein (G protein), beta 5 MYO5C 15q21 myosin VC MYO5A 15q21.1 myosin VA (heavy polypeptide 12, myoxin) EEF1B1 15q15.1-q15.3 eukaryotic translation elongation factor 1 beta 1 ARPP-19 15q15.3 eukaryotic translation elongation factor 1 beta 1 FLJ10980 15q21.1 hypothetical protein FLJ10980 ONECUT1 15q21.1-q21.2 one cut domain, family member 1
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
20 - 5704 - 1118 - 2007 17711858
21 - 5866 - 1118 - 2007 17711858
20 - 5564 - 1118 - 2007 17711858
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestivesalivary gland   highly
 stomach   highly
Hearing/Equilibriumearinnercochlea highly
Reproductivemale systemmale genital tractepididymis   Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Reproductivespermatozoa Homo sapiens
cell lineage myeloid cell lines
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a Microtubule Interacting and Transport (MIT) domain at the N terminus that constitutes an endosomal localization signal, dispensable for its catalytic activity but essential for its localization to endosomes
  • a CHMP binding (domain dispensable for its catalytic activity but is essential for its localization to endosomes)
  • a rhodanese domain
  • C-terminal catalytic domain of USP8 exhibits the conserved tripartite architecture but shows unique traits
  • HOMOLOGY
    intraspecies paralog to ubiquitin specific protein proteases UBP
    paralog to tre oncogene
    Homologene
    FAMILY
  • deubiquitin family
  • peptidase c19 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • ubiquitin specific protease, hydrolyzing isopeptide bonds between UB and folded protein domains such as additional UB mioetis or target proteins
  • its function is essential for growth factor receptor down-regulation, and regulation of endosomal ubiquitin dynamics is essential for receptor down-regulation
  • regulates the level of protein ubiquitination on endosomes, which is required for maintaining the morphology of the organelle
  • can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation
  • regulating endosomal ubiquitin dynamics and essential for receptor down-regulation
  • playing central and nonredundant role in growth regulation, endosomal sorting, and the control of several growth factor receptor tyrosine kinases (RTKs)
  • regulates cargo sorting and membrane traffic at early endosomes
  • with STAMBP are essential for trafficking and down-regulation of F2RL1 but not for regulating F2RL1 dissociation from beta-arrestin2 or F2RL1-mediated ERK2 activation
  • regulator of HGS function with consequences for the stability of receptors subject to HGS-dependent endocytosis
  • deubiquitinating activity of USP8 is required for trafficking of CXCR4 between the early and late endosomal compartments
  • modulates HGS ubiquitination to regulate endosomal ubiquitin dynamics and trafficking through the ESCRT-0 checkpoint
  • implicated in control of a highly topical and medically relevant plasma membrane receptor
  • USP8 regulates the rate of KCNN4 degradation by deubiquitylating KCNN4 prior to lysosomal delivery
  • positive regulator in HH signaling by down-regulating SMO ubiquitination and thereby mediating SMO intracellular trafficking
  • role for USP8 in the control of SCNN1A ubiquitination and trafficking
  • controls the trafficking and sorting of lysosomal enzymes
  • is critical for parkin-mediated mitophagy
  • preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy
  • BIRC6 and USP8 are two hitherto uncharacterized critical DNA damage response (DDR) regulators
  • USP8-sorted cargo contributes early to acrosomogenesis and its trafficking is microtubule-mediated
  • CELLULAR PROCESS protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    text the MIT domain is required for efficient epidermal growth factor receptor degradation
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacts with the SH3 domain of STAM2
  • interacts with RASGRF1
  • interacting with RNF41, specific target for the USP8 deubiquitinating enzyme and are consistent with a model where USP8 activate RNF41 activity by mediating its stabilization
  • interacting with CHMP1A, CHMP1B or CHMP7
  • can interact with CHMP proteins, which are known to regulate endosomal sorting of ubiquitinated receptors
  • interacting with RNF41 hthrough the rhodanese domain
  • associates with STAM to mediate direct deubiquitination of activated EGFR, thereby stabilizing the receptor against down-regulation by the lysosome
  • cooperation between USP8, ITCH, and the ESCRT-0 machinery in shaping receptor progression through the sorting endosome
  • positive regulator of CXCR4 trafficking for degradation
  • time-dependent association between KCNN4 and USP8 following endocytosis
  • interacting with SMO (overexpression of USP8 prevents SMO ubiquitination and elevates SMO accumulation, leading to increased HH signaling activity)
  • RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins
  • USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for PARK2-mediated mitophagy
  • BIRC6 acts as a scaffold, bridging the ubiquitin-specific peptidase 8 (USP8) and MCPH1 in a complex to coordinate USP8-catalyzed deubiquitination of MCPH1
  • USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501
  • USP8 interacts with and deubiquitinates SEC31A; the interaction was mediated by the adaptor protein STAM
  • cell & other
    REGULATION
    inhibited by YWHAE (catalytically inhibited in a phosphorylation-dependent manner by 14-3-3s during the interphase, and this regulation is cancelled in the M phase)
    Other is post-translationally modified by tyrosine and serine phosphorylation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    leads to diminished CXCR4 turnover and induces receptor accumulation on enlarged HGS-positive early endosomes
    constitutional somatic mutation     gain of function
    contribute to ACTH overproduction in Cushing disease
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    tumor  
    inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma
    ANIMAL & CELL MODELS