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

Fang, Nancy N. and Chan, Gerard T. and Zhu, Mang and Comyn, Sophie A. and Persaud, Avinash and Deshaies, Raymond J. and Rotin, Daniela and Gsponer, Joerg and Mayor, Thibault (2014) Rsp5/​Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress. Nature Cell Biology, 16 (12). pp. 1227-1237. ISSN 1465-7392. PMCID PMC5224936. https://resolver.caltech.edu/CaltechAUTHORS:20140915-125611389

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[img] Image (JPEG) (Supplementary Figure 1: ​Rsp5 is required for the increased ubiquitination induced by HS) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 2: Lower levels of ​Nedd4 affect the increased ubiquitination but not cell viability on HS) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 3: ​Rsp5 ubiquitinates mainly cytosolic proteins on HS without the help of arrestin-containing proteins) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 4: ​Rsp5 and ​Hul5 are mainly required for the increased ubiquitination of different proteins) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 5: The heat-induced degradation of short-lived proteins requires functional proteasome) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 6: The ​Ydj1 Hsp40 is required for the increased ubiquitination induced by HS) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 7: A destabilizing mutation near a PY-motif of ​Cdc19 induces proteasome degradation) - Supplemental Material
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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/ncb3054DOIArticle
http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3054.htmlPublisherArticle
http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3054.html#supplementary-informationPublisherSupplementary information
http://rdcu.be/cl0oPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224936PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2014 Macmillan Publishers Limited. Received 07 January 2014. Accepted 17 September 2014. Published online 26 October 2014. We thank N. Stoynov for his support for the mass spectrometry analyses, all colleagues cited in Methods who provided reagents and a previous anonymous reviewer who suggested investigating Rsp5. This work was supported by a CIHR grant. R.J.D. is an HHMI investigator and T.M. is a CIHR and MSFHR new investigator.
Funders:
Funding AgencyGrant Number
Canadian Institutes of Health Research (CIHR)UNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Michael Smith Foundation for Health Research (MSFHR)UNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC5224936
Record Number:CaltechAUTHORS:20140915-125611389
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140915-125611389
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:49715
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:29 Oct 2014 21:56
Last Modified:03 Oct 2019 07:16

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