Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae

Abstract Proteostasis promotes viability at both the cellular and organism levels by maintaining a functional proteome. This requires an intricate protein quality control (PQC) network that mediates protein folding by molecular chaperones and removes terminally misfolded proteins via the ubiquitin p...

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Autores principales:	Sophie A. Comyn, Stéphane Flibotte, Thibault Mayor
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64f77dfa53a840999b4b6e1865581fdb
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spelling	oai:doaj.org-article:64f77dfa53a840999b4b6e1865581fdb2021-12-02T16:06:36ZRecurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae10.1038/s41598-017-04525-82045-2322https://doaj.org/article/64f77dfa53a840999b4b6e1865581fdb2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04525-8https://doaj.org/toc/2045-2322Abstract Proteostasis promotes viability at both the cellular and organism levels by maintaining a functional proteome. This requires an intricate protein quality control (PQC) network that mediates protein folding by molecular chaperones and removes terminally misfolded proteins via the ubiquitin proteasome system and autophagy. How changes within the PQC network can perturb proteostasis and shift the balance between protein folding and proteolysis remain poorly understood. However, given that proteostasis is altered in a number of conditions such as cancer and ageing, it is critical that we identify the factors that mediate PQC and understand the interplay between members of the proteostatic network. In this study, we investigated the degradation of a thermally unstable cytosolic model substrate and identified a surprisingly high number of strains in the yeast knockout collection that displayed impaired turnover of the misfolded substrate. We found that this phenotype was caused by frequent background mutations in the general stress response gene WHI2. We linked this proteostatic defect to the lack of activity of the stress response transcription factor Msn2, potentially under conditions where the TOR pathway is active. Our results underscore how changes to the elaborate PQC network can perturb proteostasis and impair degradation of misfolded cytosolic proteins.Sophie A. ComynStéphane FlibotteThibault MayorNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sophie A. Comyn Stéphane Flibotte Thibault Mayor Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
description	Abstract Proteostasis promotes viability at both the cellular and organism levels by maintaining a functional proteome. This requires an intricate protein quality control (PQC) network that mediates protein folding by molecular chaperones and removes terminally misfolded proteins via the ubiquitin proteasome system and autophagy. How changes within the PQC network can perturb proteostasis and shift the balance between protein folding and proteolysis remain poorly understood. However, given that proteostasis is altered in a number of conditions such as cancer and ageing, it is critical that we identify the factors that mediate PQC and understand the interplay between members of the proteostatic network. In this study, we investigated the degradation of a thermally unstable cytosolic model substrate and identified a surprisingly high number of strains in the yeast knockout collection that displayed impaired turnover of the misfolded substrate. We found that this phenotype was caused by frequent background mutations in the general stress response gene WHI2. We linked this proteostatic defect to the lack of activity of the stress response transcription factor Msn2, potentially under conditions where the TOR pathway is active. Our results underscore how changes to the elaborate PQC network can perturb proteostasis and impair degradation of misfolded cytosolic proteins.
format	article
author	Sophie A. Comyn Stéphane Flibotte Thibault Mayor
author_facet	Sophie A. Comyn Stéphane Flibotte Thibault Mayor
author_sort	Sophie A. Comyn
title	Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
title_short	Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
title_full	Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
title_fullStr	Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
title_full_unstemmed	Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae
title_sort	recurrent background mutations in whi2 impair proteostasis and degradation of misfolded cytosolic proteins in saccharomyces cerevisiae
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/64f77dfa53a840999b4b6e1865581fdb
work_keys_str_mv	AT sophieacomyn recurrentbackgroundmutationsinwhi2impairproteostasisanddegradationofmisfoldedcytosolicproteinsinsaccharomycescerevisiae AT stephaneflibotte recurrentbackgroundmutationsinwhi2impairproteostasisanddegradationofmisfoldedcytosolicproteinsinsaccharomycescerevisiae AT thibaultmayor recurrentbackgroundmutationsinwhi2impairproteostasisanddegradationofmisfoldedcytosolicproteinsinsaccharomycescerevisiae
_version_	1718384963197337600

Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae

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