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Aggregation of Human S100A8 and S100A9 Amyloidogenic Proteins Perturbs Proteostasis in a Yeast Model
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 3, s. e58218-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Amyloid aggregates of the calcium-binding EF-hand proteins, S100A8 and S100A9, have been found in the corpora amylacea of patients with prostate cancer and may play a role in carcinogenesis. Here we present a novel model system using the yeast Saccharomyces cerevisiae to study human S100A8 and S100A9 aggregation and toxicity. We found that S100A8, S100A9 and S100A8/9 cotransfomants form SDS-resistant non-toxic aggregates in yeast cells. Using fluorescently tagged proteins, we showed that S100A8 and S100A9 accumulate in foci. After prolonged induction, S100A8 foci localized to the cell vacuole, whereas the S100A9 foci remained in the cytoplasm when present alone, but entered the vacuole in cotransformants. Biochemical analysis of the proteins indicated that S100A8 and S100A9 alone or coexpressed together form amyloid-like aggregates in yeast. Expression of S100A8 and S100A9 in wild type yeast did not affect cell viability, but these proteins were toxic when expressed on a background of unrelated metastable temperature-sensitive mutant proteins, Cdc53-1p, Cdc34-2p, Srp1-31p and Sec27-1p. This finding suggests that the expression and aggregation of S100A8 and S100A9 may limit the capacity of the cellular proteostasis machinery. To test this hypothesis, we screened a set of chaperone deletion mutants and found that reducing the levels of the heat-shock proteins Hsp104p and Hsp70p was sufficient to induce S100A8 and S100A9 toxicity. This result indicates that the chaperone activity of the Hsp104/Hsp70 bi-chaperone system in wild type cells is sufficient to reduce S100A8 and S100A9 amyloid toxicity and preserve cellular proteostasis. Expression of human S100A8 and S100A9 in yeast thus provides a novel model system for the study of the interaction of amyloid deposits with the proteostasis machinery.

Ort, förlag, år, upplaga, sidor
Public Library of Science , 2013. Vol. 8, nr 3, s. e58218-
Nationell ämneskategori
Biofysik
Forskningsämne
biokemi
Identifikatorer
URN: urn:nbn:se:umu:diva-70350DOI: 10.1371/journal.pone.0058218ISI: 000316936100091OAI: oai:DiVA.org:umu-70350DiVA, id: diva2:633793
Tillgänglig från: 2013-06-27 Skapad: 2013-05-14 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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