title: Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast.
abstract: Several metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg,  Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Jacobson
authors.forename: Clara
authors.initials: C
authors.lastname: Navarrete
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Theodora C
authors.initials: TC
authors.lastname: Sideri
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ibstedt
authors.forename: Smriti
authors.initials: S
authors.lastname: Priya
authors.forename: Chris M
authors.initials: CM
authors.lastname: Grant
authors.forename: Philipp
authors.initials: P
authors.lastname: Christen
authors.forename: Pierre
authors.initials: P
authors.lastname: Goloubinoff
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Tamás
mesh_terms: D018053:Arsenites / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049409:Luciferases, Firefly / Q000096:biosynthesis; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018053:Arsenites; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D049409:Luciferases, Firefly; D046988:Proteasome Endopeptidase Complex; C015001:arsenite