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1339148 
Journal Article 
Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast 
Jacobson, T; Navarrete, C; Sharma, SK; Sideri, TC; Ibstedt, S; Priya, S; Grant, CM; Christen, P; Goloubinoff, P; Tamás, MJ 
In Press 
Yes 
Journal of Cell Science
ISSN: 0021-9533
EISSN: 1477-9137 
125 
21 
5073-5083 
English 
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. 
Arsenic toxicity; Protein aggregation; Protein degradation; Protein folding; Yeast 
IRIS
• Arsenic Hazard ID
     1. Initial Lit Search
          PubMed
          WOS
          Considered New
     2. Lit Search Updates through Oct 2015
          WOS
          Considered
     4. Considered through Oct 2015
     6. Cluster Filter through Oct 2015
     7. Other Studies through Oct 2015
          MOA
• Arsenic (Inorganic)
     1. Literature
          PubMed
          Lit search updates through Oct 2015
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
          Excluded/Not relevant
               Title/Abstract screening
• Arsenic MOA
     1. MOA Literature Screening
          Health Effect Screening
     3. Excluded
          Other not relevant
               Dragon Screened