The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein

Daniel W Summers; Katie J Wolfe; Hong Yu Ren; Douglas M Cyr

doi:10.1371/journal.pone.0052099

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The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein

Journal article

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The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein

Daniel W Summers, Katie J Wolfe, Hong Yu Ren and Douglas M Cyr

PloS one, Vol.8(1), pp.e52099-e52099

2013

DOI: 10.1371/journal.pone.0052099

PMCID: PMC3547041

PMID: 23341891

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Abstract

Mechanisms for cooperation between the cytosolic Hsp70 system and the ubiquitin proteasome system during protein triage are not clear. Herein, we identify new mechanisms for selection of misfolded cytosolic proteins for degradation via defining functional interactions between specific cytosolic Hsp70/Hsp40 pairs and quality control ubiquitin ligases. These studies revolved around the use of S. cerevisiae to elucidate the degradation pathway of a terminally misfolded reporter protein, short-lived GFP (slGFP). The Type I Hsp40 Ydj1 acts with Hsp70 to suppress slGFP aggregation. In contrast, the Type II Hsp40 Sis1 is required for proteasomal degradation of slGFP. Sis1 and Hsp70 operate sequentially with the quality control E3 ubiquitin ligase Ubr1 to target slGFP for degradation. Compromise of Sis1 or Ubr1 function leads slGFP to accumulate in a Triton X-100-soluble state with slGFP degradation intermediates being concentrated into perinuclear and peripheral puncta. Interestingly, when Sis1 activity is low the slGFP that is concentrated into puncta can be liberated from puncta and subsequently degraded. Conversely, in the absence of Ubr1, slGFP and the puncta that contain slGFP are relatively stable. Ubr1 mediates proteasomal degradation of slGFP that is released from cytosolic protein handling centers. Pathways for proteasomal degradation of misfolded cytosolic proteins involve functional interplay between Type II Hsp40/Hsp70 chaperone pairs, PQC E3 ligases, and storage depots for misfolded proteins.

Amino Acid Sequence

Green Fluorescent Proteins - metabolism

HSP40 Heat-Shock Proteins - metabolism

Ubiquitin - metabolism

Ubiquitin-Protein Ligases - metabolism

Adenosine Triphosphatases - metabolism

Molecular Sequence Data

Saccharomyces cerevisiae - drug effects

Cycloheximide - pharmacology

HSP70 Heat-Shock Proteins - metabolism

Saccharomyces cerevisiae - metabolism

Proteolysis - drug effects

Substrate Specificity - drug effects

Protein Folding - drug effects

Saccharomyces cerevisiae Proteins - metabolism

Cytosol - metabolism

Proteasome Endopeptidase Complex - metabolism

Protein Stability

Green Fluorescent Proteins - chemistry

Details

Title: Subtitle: The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein
Creators: Daniel W Summers - Department of Cell and Developmental Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Katie J Wolfe
Hong Yu Ren
Douglas M Cyr
Resource Type: Journal article
Publication Details: PloS one, Vol.8(1), pp.e52099-e52099
DOI: 10.1371/journal.pone.0052099
PMID: 23341891
PMCID: PMC3547041
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: United States
Grant note: 5F31NS074777-02 / NINDS NIH HHS R01 GM056981 / NIGMS NIH HHS 5F31AG032790-02 / NIA NIH HHS
Language: English
Date published: 2013
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9983992052902771

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