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

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. Mayor and colleagues identify yeast Rsp5 (mammalian homologue Nedd4) as the main ubiquitin ligase responsible for the increased ubiquitylation following heat stress when Rsp5 targets cytosolic misfolded proteins for proteasome degradation.

Cite this article

Fang, N., Chan, G., Zhu, M. et al. Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress. Nat Cell Biol 16, 1227–1237 (2014). https://doi.org/10.1038/ncb3054

View full text

>> Full Text:   Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat str