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Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility

Comyn, Sophie A ; Young, Barry P ; Loewen, Christopher J ; Mayor, Thibault Gardner, Richard

PLoS genetics, 2016-07, Vol.12 (7), p.e1006184 [Revista revisada por pares]

United States: Public Library of Science

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Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility
Autor: Comyn, Sophie A ; Young, Barry P ; Loewen, Christopher J ; Mayor, Thibault
Gardner, Richard
Materias: Alzheimer's disease ; Alzheimers disease ; Biology and Life Sciences ; Engineering and Technology ; Experiments ; Flow cytometry ; Gene mutation ; Gene mutations ; Guanylate Kinases - genetics ; Homeostasis ; Molecular Chaperones - genetics ; Mutation ; Mutation, Missense ; Observations ; Physical Sciences ; Physiological aspects ; Plasmids ; Polypeptides ; Proteasome Endopeptidase Complex - genetics ; Proteasome Endopeptidase Complex - metabolism ; Protein Aggregates - genetics ; Protein Folding ; Proteolysis ; Quality control ; Research and Analysis Methods ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - genetics ; Solubility ; Standard deviation ; Ubiquitin-proteasome system ; Ubiquitin-Protein Ligases - genetics ; Ubiquitination ; Yeast
Es parte de: PLoS genetics, 2016-07, Vol.12 (7), p.e1006184
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: SAC BPY CJL TM. Performed the experiments: SAC. Analyzed the data: SAC TM. Contributed reagents/materials/analysis tools: SAC BPY CJL TM. Wrote the paper: SAC BPY CJL TM.
The authors have declared that no competing interests exist.
Descripción: Misfolded proteins challenge the ability of cells to maintain protein homeostasis and can accumulate into toxic protein aggregates. As a consequence, cells have adopted a number of protein quality control pathways to prevent protein aggregation, promote protein folding, and target terminally misfolded proteins for degradation. In this study, we employed a thermosensitive allele of the yeast Guk1 guanylate kinase as a model misfolded protein to investigate degradative protein quality control pathways. We performed a flow cytometry based screen to identify factors that promote proteasomal degradation of proteins misfolded as the result of missense mutations. In addition to the E3 ubiquitin ligase Ubr1, we identified the prefoldin chaperone subunit Gim3 as an important quality control factor. Whereas the absence of GIM3 did not impair proteasomal function or the ubiquitination of the model substrate, it led to the accumulation of the poorly soluble model substrate in cellular inclusions that was accompanied by delayed degradation. We found that Gim3 interacted with the Guk1 mutant allele and propose that prefoldin promotes the degradation of the unstable model substrate by maintaining the solubility of the misfolded protein. We also demonstrated that in addition to the Guk1 mutant, prefoldin can stabilize other misfolded cytosolic proteins containing missense mutations.
Editor: United States: Public Library of Science
Idioma: Inglés

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Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility

Comyn, Sophie A ; Young, Barry P ; Loewen, Christopher J ; Mayor, Thibault Gardner, Richard

United States: Public Library of Science

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