VCP

This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

Valosin Containing Protein

Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). 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 (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908).
Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (PubMed:29804830).
Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites (PubMed:22020440, PubMed:22120668).
Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage (PubMed:23042607, PubMed:23042605).
Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis (PubMed:32152270).
Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex (By similarity).
Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal (PubMed:35013556).
Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995).
Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy (PubMed:20104022, PubMed:27753622).
Acts as a negative regulator of type I interferon production by interacting with RIGI: interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI (PubMed:26471729).
May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation (PubMed:21822278).
May more particularly play a role in caveolins sorting in cells (PubMed:21822278, PubMed:23335559).
By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).

Biological Process activation of cysteine-type endopeptidase activity involved in apoptotic process Source:UniProtKB
Biological Process aggresome assembly Source:Ensembl
Biological Process ATP metabolic process Source:Ensembl
Biological Process autophagosome maturation Source:UniProtKB1 Publication
Biological Process autophagy Source:UniProtKB2 Publications
Biological Process cellular response to arsenite ion Source:UniProtKB1 Publication
Biological Process cellular response to DNA damage stimulus Source:UniProtKB3 Publications
Biological Process cellular response to heat Source:UniProtKB1 Publication
Biological Process DNA repair Source:UniProtKB1 Publication
Biological Process double-strand break repair Source:UniProtKB2 Publications
Biological Process endoplasmic reticulum stress-induced pre-emptive quality control Source:UniProtKB1 Publication
Biological Process endoplasmic reticulum to Golgi vesicle-mediated transport Source:Ensembl
Biological Process endoplasmic reticulum unfolded protein response Source:UniProtKB1 Publication
Biological Process endosome to lysosome transport via multivesicular body sorting pathway Source:UniProtKB1 Publication
Biological Process ER-associated misfolded protein catabolic process Source:ParkinsonsUK-UCL1 Publication
Biological Process ERAD pathway Source:ParkinsonsUK-UCL1 Publication
Biological Process establishment of protein localization Source:UniProtKB1 Publication
Biological Process flavin adenine dinucleotide catabolic process Source:ParkinsonsUK-UCL1 Publication
Biological Process interstrand cross-link repair Source:UniProtKB
Biological Process macroautophagy Source:UniProtKB1 Publication
Biological Process mitotic spindle disassembly Source:GO_Central1 Publication
Biological Process NADH metabolic process Source:ParkinsonsUK-UCL1 Publication
Biological Process negative regulation of smoothened signaling pathway Source:FlyBase1 Publication
Biological Process positive regulation of ATP biosynthetic process Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of canonical Wnt signaling pathway Source:FlyBase1 Publication
Biological Process positive regulation of Lys63-specific deubiquitinase activity Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of mitochondrial membrane potential Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of oxidative phosphorylation Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source:BHF-UCL1 Publication
Biological Process positive regulation of protein catabolic process Source:BHF-UCL2 Publications
Biological Process positive regulation of protein K63-linked deubiquitination Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of protein-containing complex assembly Source:BHF-UCL1 Publication
Biological Process proteasomal protein catabolic process Source:UniProtKB1 Publication
Biological Process proteasome-mediated ubiquitin-dependent protein catabolic process Source:UniProtKB1 Publication
Biological Process protein ubiquitination Source:UniProtKB1 Publication
Biological Process protein-DNA covalent cross-linking repair Source:UniProtKB1 Publication
Biological Process regulation of aerobic respiration Source:ParkinsonsUK-UCL1 Publication
Biological Process regulation of apoptotic process Source:UniProtKB1 Publication
Biological Process regulation of protein localization to chromatin Source:UniProtKB1 Publication
Biological Process regulation of synapse organization Source:Ensembl
Biological Process retrograde protein transport, ER to cytosol Source:UniProtKB1 Publication
Biological Process stress granule disassembly Source:UniProtKB1 Publication
Biological Process translesion synthesis Source:UniProtKB1 Publication
Biological Process ubiquitin-dependent ERAD pathway Source:UniProtKB1 Publication
Biological Process viral genome replication Source:CACAO1 Publication

Cytoplasm, cytosol
Endoplasmic reticulum
Nucleus
Cytoplasm, Stress granule
Present in the neuronal hyaline inclusion bodies specifically found in motor neurons from amyotrophic lateral sclerosis patients (PubMed:15456787).
Present in the Lewy bodies specifically found in neurons from Parkinson disease patients (PubMed:15456787).
Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78 (PubMed:16168377).
Following DNA double-strand breaks, recruited to the sites of damage (PubMed:22120668).
Recruited to stalled replication forks via interaction with SPRTN (PubMed:23042605).
Recruited to damaged lysosomes decorated with K48-linked ubiquitin chains (PubMed:27753622).
Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules (SGs) in response to arsenite-induced stress treatment (PubMed:29804830).

Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1):
An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (FTDALS6):
A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia (FTD) is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis (ALS) is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS6 is an autosomal dominant form characterized by onset of ALS or FTD in adulthood. Some patients with the disorder may have features of both diseases.
Charcot-Marie-Tooth disease 2Y (CMT2Y):
An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy.

Phosphorylated by tyrosine kinases in response to T-cell antigen receptor activation. Phosphorylated in mitotic cells.
ISGylated.
Methylation at Lys-315 catalyzed by VCPKMT is increased in the presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity.