The Cdc48-Vms1 complex maintains 26S proteasome architecture

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 multi-catalytic 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. Cdc48 also associates with numerous co-factors, but to date it is unclear whether each cofactor facilitates proteasome delivery. We discovered that yeast lacking a conserved Cdc48 cofactor, Vms1, 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 stationary phase. Our findings highlight an unexpected link between the Cdc48-Vms1 complex and the preservation of proteasome architecture, and indicate how perturbed proteasome assembly impacts the turnover of ubiquitinated proteins and maintains viability in ageing cells.

Source: BJ Cell - December 19, 2013 Category: Biochemistry Authors: J R Tran, J L Brodsky Tags: BJ Cell Source Type: research