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Nat Cell Biol. 2014 Dec;16(12):1227-37. doi: 10.1038/ncb3054. Epub 2014 Oct 26.

Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress.

Author information

1
Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, 2125 East Mall Vancouver, British Columbia V6T1Z4, Canada.
2
Program in Cell Biology, Hospital for Sick Children, and Biochemistry Department, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
3
Howard Hughes Medical Institute, Division of Biology and Biological Engineering, 114-96 Caltech, 1200 E. California Boulevard Pasadena, California 91125, USA.

Abstract

The heat-shock response is a complex cellular program that induces major changes in protein translation, folding and degradation to alleviate toxicity caused by protein misfolding. Although heat shock has been widely used to study proteostasis, it remained unclear how misfolded proteins are targeted for proteolysis in these conditions. We found that Rsp5 and its mammalian homologue Nedd4 are important E3 ligases responsible for the increased ubiquitylation induced by heat stress. We determined that Rsp5 ubiquitylates mainly cytosolic misfolded proteins upon heat shock for proteasome degradation. We found that ubiquitylation of heat-induced substrates requires the Hsp40 co-chaperone Ydj1 that is further associated with Rsp5 upon heat shock. In addition, ubiquitylation is also promoted by PY Rsp5-binding motifs found primarily in the structured regions of stress-induced substrates, which can act as heat-induced degrons. Our results support a bipartite recognition mechanism combining direct and chaperone-dependent ubiquitylation of misfolded cytosolic proteins by Rsp5.

PMID:
25344756
PMCID:
PMC5224936
DOI:
10.1038/ncb3054
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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