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FLASH GENE
Symbol VCP contributors: mct/npt/pgu - updated : 28-06-2020
HGNC name valosin-containing protein
HGNC id 12666
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveintestinesmall intestine  highly
Nervousbrain   highly
Skin/Tegumentskin   highly
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a N-domain involved in ubiquitin and cofactor binding (N domain is the binding site of the UBX and structurally related UBX-like domains) , N-domain followed by a D1 and D2 domain
  • two AAA domains chaperone like adenosine triphosphatases (ATPase associated with diverse cellular activities)
  • two major sites of cofactor interactions: the amino-terminal N domain and the carboxy-terminal tail
    • mono polymer hexamer
    HOMOLOGY
    interspecies homolog to murine Vcp (99.9pc)
    homolog to rattus Vcp (99.9pc)
    Homologene
    FAMILY
  • type II AAA+ ATPase family
    • CATEGORY chaperone/stress , structural protein
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic,vesicle
    intracellular,nucleus
    text
  • a fraction of VCP is localized to the early endosome membrane, where it binds EEA1 via the N-terminal C2H2 zinc finger domain
  • SIK2 co-localizes with VCP in the ER membrane
    • basic FUNCTION
  • homohexameric AAA (ATPase associated with a variety of activities)
  • vesicular transport and fusion
  • involved in the transfer of membranes from the endoplasmic reticulum to the golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum
  • implicated in a number of cellular events that are regulated during mitosis, including homotypic membrane fusion, spindle pole body function, and ubiquitin-dependent protein degradation
  • participating in a number of cellular processes including endoplasmic reticulum-associated degradation (ERAD)
  • multiubiquitin chain-targeting factor in the degradation of the ubiquitin-proteasome pathway
  • binding to an ubiquitylated form of Aurora B on chromatin, resulting in extraction of Aurora B from chromatin, allowing chromosome decondensation and nuclear envelope formation
  • essential biochemical component of a wide range of ubiquitin-linked cell biological reactions, including ubiquitin-proteasome system-mediated protein degradation, Golgi and endoplasmic reticulum (ER) membrane fusion, transcription factor activation, and DNA repair
  • having functions in endocytic trafficking by establishing EEA1 as a new VCP substrate
  • may regulate the size of early endosomes by governing the oligomeric state of EEA1
  • cooperates with distinct cofactors to process ubiquitylated proteins in different cellular pathways
  • cytosolic essential AAA chaperone, which regulates multiple cellular reactions in a ubiquitin-dependent manner
  • important role in ubiquitin-dependent regulation of translesion synthesis
  • VCP is an important host factor in antiviral immunity
  • VCP has a crucial role in proteasomal degradation of viral capsid
  • is an essential cofactor for antibody-dependent intracellular neutralization (ADIN) and the ATPase activity of VCP is required when ADIN mediates proteasomal degradation of a challenging substrate such as an adenovirus particle
  • has a crucial role in proteasomal degradation of viral capsid
  • FAF2 and VCP play central integrative roles in cellular energy homeostasis
  • acts downstream of ubiquitination and is required for transport of the ubiquitinated form of CAV1 to late endosomes
  • conserved chaperone-like ATPase, plays a strategic role in the ubiquitin system
  • AAA ATPase involved in protein turnover and degradation
  • VCP-dependent protein extraction from chromatin has emerged as an essential evolutionarily conserved process for maintaining genome stability
  • its depletion or pathogenic mutations reducing stress granule clearance in mammalian cells
  • VCP and YOD1 are required in the downstream events of substrate deglycosylation and proteasomal degradation (
  • important role for VCP in early autophagy initiation
  • critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote outer mitochondrial membrane protein degradation and eventual mitophagy
  • involved in the fusion of early endosomes and endolysosomal degradation
  • promotes not only the lysosomal degradation, but also the recycling of endocytic cargo
  • ubiquitous AAA+ protein (ATPase associated with other activities) that facilitates protein degradation through the ubiquitin-proteasome and autophagy pathways
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cellular trafficking transport
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with clathrin, and heat-shock protein Hsc70
  • VCP complex with the UBXN6 cofactor, which binds to the plasma membrane protein CAV1 and whose formation is specifically disrupted by disease-associated mutations
  • member of the mammalian ERAD complex composed of Derlins, SELS, and SELK
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • bound with high affinity to clathrin
  • with complex DER1/ VIMP that serves as a receptor for VCP
  • binding to ATXN3
  • binding partner of FAF1
  • HIF1A is the first endogenous substrate of VCP that is not associated with the ER
  • interacting with TARDBP (VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TARDBP)
  • ER lumenal domain of MKS3 interacted with a complex that included mutant SFTPC and associated chaperones, whereas the region predicted to encode the transmembrane domains of MKS3 interacted with cytosolic VCP
  • NSFL1C is a VCP-binding protein, that functions in Golgi membrane fusion together with VCP and VCPIP1, another VCP-binding protein
  • potential synergistic cooperation between VCP and ATXN3 in ubiquitin-mediated proteolysis and ageing regulation
  • ASPSCR1 controls VCP oligomeric status at a particular location in the early secretory pathway and in which this process regulates membrane trafficking in various cell types
  • is an activator specifically of wild-type ATXN3, exhibiting no effect on expanded ATXN3
  • VCP regulation by PTPN13 might be important for tumorigenesis
  • SPRTN recruits VCP to sites of DNA damage
  • VCP, an enzyme with segregase and unfoldase activity, is a key player in TRIM21-mediated virus neutralization
  • function directly with 20S peptidase to maintain intracellular protein quality control
  • directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence
  • UBXN2B/NSFL1C adaptors of VCP regulate mitosis by limiting the centrosomal recruitment of AURKA
  • NUB1L directly interacted with NEDD8, but not with ubiquitin, on the key residue Asn-51 of NEDD8 and with VCP on its positively charged VCP binding motif
  • SIK2 co-localizes with VCP in the ER membrane and stimulates its ATPase activity through direct phosphorylation
  • proteasome-mediated processing of NFE2L1 is essential for coordinate induction of all proteasome subunits and VCP
  • interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP, SFPQ, UBA1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12)
  • VCP/p97 cooperates with YOD1, UBXN6 and PLAA to drive clearance of ruptured lysosomes by autophagy
  • UBXN7, adaptor of VCP ATPase, can participate in the degradation of misfolded or damaged proteins in the VCP-mediated ubiquitin proteasome system (UPS)
  • may have a cooperative effect on VCP interaction with UFD1L
  • METTL21C trimethylates VCP on the Lys315 residue and loss of this modification reduced VCP hexamer formation and ATPase activity
  • VCP-ATXN3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions
  • VCP stabilizes BECN1 levels by promoting the deubiquitinase activity of ATXN3 towards BECN1
  • WIPI2 binds to and promotes AAA-ATPase VCP/p97 to damaged mitochondria
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) IBMPFD , ALS14 , CMT2Y , DDHDM
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    functional defect of VCP in DNA double-stranded break repair is critical for the pathology of neurons in which VCP is located dominantly in the nucleus
    constitutional       loss of function
    causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption, resulting in a significant reduction of cellular ATP production
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS