title: Protein aggregation activates erratic stress response in dietary restricted yeast cells.
abstract: Chronic stress and prolonged activation of defence pathways have deleterious consequences for the cell. Dietary restriction is believed to be beneficial as it induces the cellular stress response machinery. We report here that although the phenomenon is beneficial in a wild-type cell, dietary restriction leads to an inconsistent response in a cell that is already under proteotoxicity-induced stress. Using a yeast model of Huntington's disease, we show that contrary to expectation, aggregation of mutant huntingtin is exacerbated and activation of the unfolded protein response pathway is dampened under dietary restriction. Global proteomic analysis shows that when exposed to a single stress, either protein aggregation or dietary restriction, the expression of foldases like peptidyl-prolyl isomerase, is strongly upregulated. However, under combinatorial stress, this lead is lost, which results in enhanced protein aggregation and reduced cell survival. Successful designing of aggregation-targeted therapeutics will need to take additional stressors into account.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Ankan Kumar
authors.initials: AK
authors.lastname: Bhadra
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Eshita
authors.initials: E
authors.lastname: Das
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Roy
mesh_terms: D015180:Electrophoresis, Gel, Two-Dimensional; D018869:Heat-Shock Response; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism; D050296:Microbial Viability; D050505:Mutant Proteins / Q000378:metabolism; D010641:Phenotype; D066329:Protein Aggregates; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013312:Stress, Physiological; D056811:Unfolded Protein Response
chemical_list: D000071058:Huntingtin Protein; D050505:Mutant Proteins; D066329:Protein Aggregates; D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins