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Abstract
The ubiquitin–proteasome (Ub-Pr) degradation pathway regulates many cellular activities1,2, 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 κB inhibitor, IκBα to the proteasome for degradation3. VCP4 is an abundant and a highly conserved member of the AAA (ATPases associated with a variety of cellular activities) family5,6,7. 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.Cite this article
Dai, R., Li, CC. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin–proteasome degradation. Nat Cell Biol 3, 740–744 (2001). https://doi.org/10.1038/35087056 