title: The Cdc48-Vms1 complex maintains 26S proteasome architecture.
abstract: The 26S proteasome is responsible for most regulated protein turnover and for the degradation of aberrant proteins in eukaryotes. The assembly of this ~2.5 MDa multicatalytic protease requires several dedicated chaperones and, once assembled, substrate selectivity is mediated by ubiquitin conjugation. After modification with ubiquitin, substrates are escorted to the proteasome by myriad factors, including Cdc48 (cell-division cycle 48). Cdc48 also associates with numerous cofactors, but, to date, it is unclear whether each cofactor facilitates proteasome delivery. We discovered that yeast lacking a conserved Cdc48 cofactor, Vms1 [VCP (valosin-containing protein)/Cdc48-associated mitochondrial stress-responsive], accumulate proteasome-targeted ubiquitinated proteins. Vms1 mutant cells also contain elevated levels of unassembled 20S proteasome core particles and select 19S cap subunits. In addition, we found that the ability of Vms1 to support 26S proteasome assembly requires Cdc48 interaction, and that the loss of Vms1 reduced 26S proteasome levels and cell viability after prolonged culture in the stationary phase. The results of the present study highlight an unexpected link between the Cdc48-Vms1 complex and the preservation of proteasome architecture, and indicate how perturbed proteasome assembly affects the turnover of ubiquitinated proteins and maintains viability in aging cells.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Tran
authors.affiliation: *Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, U.S.A.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029701:Saccharomyces cerevisiae Proteins; D057149:Ubiquitinated Proteins; C557318:Vms1 protein, S cerevisiae; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein