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FLASH GENE

Symbol

VCP

contributors: mct/npt/pgu - updated : 28-06-2020

HGNC name	valosin-containing protein
HGNC id	12666

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	16.67 kb     17 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_007126 17 - 3198 89 806 - 2009 19506019

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine     highly Nervous brain       highly Skin/Tegument skin       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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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