Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation

Nat Cell Biol. 2001 Aug;3(8):740-4. doi: 10.1038/35087056.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases
  • Binding Sites / physiology
  • Cell Cycle / physiology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cyclin E / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Humans
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Mutation / physiology
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary / physiology
  • Schizosaccharomyces / cytology
  • Schizosaccharomyces / metabolism
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*
  • Valosin Containing Protein


  • Cell Cycle Proteins
  • Cyclin E
  • Molecular Chaperones
  • Multienzyme Complexes
  • Ubiquitins
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein