In:
Journal of Cell Science, The Company of Biologists
Abstract:
Cdc48/p97, also known as valosin-containing protein or VCP, is an abundant AAA-ATPase that is essential for many ubiquitin-dependent processes. One well-documented role for Cdc48 is facilitating the delivery of ubiquitinated, misfolded endoplasmic-reticulum proteins to the proteasome for degradation. By contrast, Cdc48's participation in misfolded protein degradation in the nucleus is unknown. In the budding yeast Saccharomyces cerevisiae, degradation of misfolded proteins in the nucleus is primarily mediated by the nuclear-localized ubiquitin-protein ligase San1, which ubiquitinates misfolded nuclear proteins for proteasomal degradation. Here, we find that, although Cdc48 is involved in the degradation of some San1 substrates, it is not universally required. The differential Cdc48 requirement correlates with San1 substrate insolubility. The more insoluble the substrate, the more its degradation requires Cdc48. Expression of Cdc48-dependent San1 substrates in mutant cdc48 cells results in increased substrate insolubility, larger inclusion formation, and reduced cell viability. Substrate ubiquitination is increased in mutant cdc48 cells, suggesting that Cdc48 functions downstream of San1. Synthesizing all of the data gathered, we propose that Cdc48 acts, in part, to maintain the solubility or reverse the aggregation of insoluble misfolded proteins prior to their proteasomal degradation.
Type of Medium:
Online Resource
ISSN:
1477-9137
,
0021-9533
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2014
detail.hit.zdb_id:
219171-4
detail.hit.zdb_id:
1483099-1
SSG:
12
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