title: Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation.
abstract: The ubiquitin-proteasome (Ub-Pr) degradation pathway regulates many cellular activities, but how ubiquitinated substrates are targeted to the proteasome is not understood. We have shown previously that valosin-containing protein (VCP) physically and functionally targets the ubiquitinated nuclear factor kappaB inhibitor, IkappaBalpha to the proteasome for degradation. VCP is an abundant and a highly conserved member of the AAA (ATPases associated with a variety of cellular activities) family. Besides acting as a chaperone in membrane fusions, VCP has been shown to have a role in a number of seemingly unrelated cellular activities. Here we report that loss of VCP function results in an inhibition of Ub-Pr-mediated degradation and an accumulation of ubiquitinated proteins. VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. Furthermore, its N-terminal domain is required in Ub-Pr-mediated degradation. We conclude that VCP is a multi-ubiquitin chain-targeting factor that is required in the degradation of many Ub-Pr pathway substrates, and provide a common mechanism that underlies many of the functions of VCP.
authors.affiliation: Intramural Research Support Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Dai
authors.forename: C C
authors.initials: CC
authors.lastname: Li
mesh_terms: D000251:Adenosine Triphosphatases; D001665:Binding Sites / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary / Q000502:physiology; D012568:Schizosaccharomyces / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein