Interdependence of amyloid formation in yeast

Urakov, Valery N.; Vishnevskaya, Aleksandra B.; Alexandrov, Ilya; Kushnirov, Vitaly V.; Смирнов, В. Н.; Ter‐Avanesyan, Michael D.

doi:10.4161/pri.4.1.11074

Cited by 34 publications

(23 citation statements)

References 46 publications

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“…This indicates a possibility of sequestration of Sup35 by the aggresome, and agrees with the previous observation [43], confirmed by us (Figure 1E) that polyglutamines promote aggregation of a fraction of Sup35, even in a [ psi − ] strain. Notably, 103QP toxicity in the [ PSI + ] cells was ameliorated by introducing the Sup35 derivative (designated Sup35C) that lacks the N-terminal (prion) and middle domains and therefore, is functional but unable to be incorporated into the prion aggregates (Figure 1F).…”

Section: Resultssupporting

confidence: 92%

Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast

et al. 2012

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Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington's disease. Fragments of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamine cytotoxicity in cells containing only the prion form of Rnq1 protein. Here we show that expanded polyglutamines both with (poly-QP) or without (poly-Q) a P-rich stretch remain toxic in the presence of the prion form of translation termination (release) factor Sup35 (eRF3). A Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into aggregates counteracts cytotoxicity, suggesting that toxicity is due to Sup35 sequestration. Increase in the levels of another release factor, Sup45 (eRF1), due to either disomy by chromosome II containing the SUP45 gene or to introduction of the SUP45-bearing plasmid counteracts poly-Q or poly-QP toxicity in the presence of the Sup35 prion. Protein analysis confirms that polyglutamines alter aggregation patterns of Sup35 and promote aggregation of Sup45, while excess Sup45 counteracts these effects. Our data show that one and the same mode of polyglutamine aggregation could be cytoprotective or cytotoxic, depending on the composition of other aggregates in a eukaryotic cell, and demonstrate that other aggregates expand the range of proteins that are susceptible to sequestration by polyglutamines.

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Section: Resultssupporting

confidence: 92%

Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast

et al. 2012

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“…This was shown for htt with a polyQ stretch consisting of 103 Q (103Q) fused to the green fluorescent protein (GFP), which allows monitoring of 103Q-GFP aggregation microscopically, as distinct fluorescent foci. However, as we have shown previously, polyQ proteins could also form SDS-insoluble polymers in cells lacking these prions ([ psi − ] [ pin − ] cells) [9], [12]. This prompted us to study the dependence of 103Q-GFP polymerization on the [ PIN + ] prion.…”

Section: Resultsmentioning

confidence: 97%

“…Previously we have shown that aggregation of proteins with expanded polyQ, including mutant htt, in the cytoplasm of yeast cells caused polymerization of chromosomally-encoded Q/N-rich proteins [9]. Since there are a large number of proteins with long Q/N-rich stretches in both humans and yeast [10], [11], it is likely that at least some of them would efficiently polymerize in response to the accumulation of polyQ amyloids, which may cause depletion of their functional soluble form and, as a result, cell death, if these proteins are essential.…”

Section: Introductionmentioning

confidence: 99%

Amyloid-Mediated Sequestration of Essential Proteins Contributes to Mutant Huntingtin Toxicity in Yeast

2012

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BackgroundPolyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN +]), which has a glutamine/asparagine-rich domain.Principal FindingsHere, we showed that aggregation and toxicity of mutant htt depended on [PIN +] only quantitatively: the presence of [PIN +] elevated the toxicity and the levels of htt detergent-insoluble polymers. In cells lacking [PIN +], toxicity of mutant htt was due to the polymerization and inactivation of the essential glutamine/asparagine-rich Sup35 protein and related inactivation of another essential protein, Sup45, most probably via its sequestration into Sup35 aggregates. However, inhibition of growth of [PIN +] cells depended on Sup35/Sup45 depletion only partially, suggesting that there are other sources of mutant htt toxicity in yeast.ConclusionsThe obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity.

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“…These model substrates share some similarities in that both are aggregationprone and they form large inclusions in yeast. Prions, such as [RNQ1] ϩ , are required for polyQ toxicity (16,17) and, likewise, polyQ aggregation influences prion formation (18). These results and many others (2,3,15).…”

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confidence: 85%

Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

Walter

Smith

Wisén

et al. 2011

Journal of Biological Chemistry

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In Saccharomyces cerevisae, expanded polyglutamine (polyQ) fragments are assembled into discrete cytosolic aggregates in a process regulated by the molecular chaperones Hsp26, Hsp70, Hsp90, and Hsp104. To better understand how the different chaperones might cooperate during polyQ aggregation, we used sequential immunoprecipitations and mass spectrometry to identify proteins associated with either soluble (Q25) or aggregation-prone (Q103) fragments at both early and later times after induction of their expression. We found that Hsp26, Hsp70, Hsp90, and other chaperones interact with Q103, but not Q25, within the first 2 h. Further, Hsp70 and Hsp90 appear to be partially released from Q103 prior to the maturation of the aggregates and before the recruitment of Hsp104. To test the importance of this seemingly ordered process, we used a chemical probe to artificially enhance Hsp70 binding to Q103. This treatment retained both Hsp70 and Hsp90 on the polyQ fragment and, interestingly, limited subsequent exchange for Hsp26 and Hsp104, resulting in incomplete aggregation. Together, these results suggest that partial release of Hsp70 may be an essential step in the continued processing of expanded polyQ fragments in yeast.The heat shock proteins (HSPs) 3 are abundant molecular chaperones that have been shown to be important for maintaining proteostasis under both normal conditions and during times of cellular stress (1-3). Together, these factors play multiple roles in quality control, especially related to polypeptide synthesis, folding, and turnover (4 -7). Moreover, HSPs are emerging as drug targets in cancer, neurodegenerative disorders and other diseases (8, 9). Thus, there is interest in better understanding how they coordinate protein quality control decisions.The major families of HSPs are named based on their approximate kDa molecular weights, including Hsp60, Hsp70, Hsp90,

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Interdependence of amyloid formation in yeast

Cited by 34 publications

References 46 publications

Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast

Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast

Amyloid-Mediated Sequestration of Essential Proteins Contributes to Mutant Huntingtin Toxicity in Yeast

Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

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