Systems Analyses Reveal Two Chaperone Networks with Distinct Functions in Eukaryotic Cells

Albanèse, Véronique; Yam, Alice; Baughman, Joshua M.; Parnot, Charles; Frydman, Judith

doi:10.1016/j.cell.2005.11.039

Cited by 232 publications

(268 citation statements)

References 60 publications

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“…We now add Pf Hsp90 to the list of heterologous Hsp90's that can apparently fulfill at least the essential functions of Hsp90 in yeast for vegetative growth in standard growth media. Whatever these functions are exactly, they must include many of the ones that have been highlighted by global biochemical and genetic analyses of Hsp90 interactions in this organism [25][26][27][28]. The results of these genetic complementation experiments underscore the high evolutionary conservation of Hsp90 [29][30][31][32].…”

Section: Discussionmentioning

confidence: 99%

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider

Péli-Gulli

Briand

et al. 2009

Molecular and Biochemical Parasitology

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Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90α or Hsp90β, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window

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Section: Discussionmentioning

confidence: 99%

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider

Péli-Gulli

Briand

et al. 2009

Molecular and Biochemical Parasitology

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“…Recent studies in eukaryotic cells suggest a mechanism for how osmotic stress-induced damage may be discriminated from other forms of protein damage. Albanese et al (34) demonstrated that eukaryotes have at least two distinct systems for detecting and repairing protein misfolding. Canonical heat-shock proteins (HSPs) function to refold stress-denatured proteins (35).…”

mentioning

confidence: 99%

“…Canonical heat-shock proteins (HSPs) function to refold stress-denatured proteins (35). In contrast, chaperones that are linked to protein synthesis (CLIPS) function to regulate de novo protein folding (34).…”

mentioning

confidence: 99%

Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression

Lamitina

Huang²,

Strange³

2006

Proc. Natl. Acad. Sci. U.S.A.

159

257

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The detection, stabilization, and repair of stress-induced damage are essential requirements for cellular life. All cells respond to osmotic stress-induced water loss with increased expression of genes that mediate accumulation of organic osmolytes, solutes that function as chemical chaperones and restore osmotic homeostasis. The signals and signaling mechanisms that regulate osmoprotective gene expression in animal cells are poorly understood. Here, we show that gpdh-1 and gpdh-2, genes that mediate the accumulation of the organic osmolyte glycerol, are essential for survival of the nematode Caenorhabditis elegans during osmotic stress. Expression of GFP driven by the gpdh-1 promoter (P gpdh-1::GFP) is detected only during hypertonic stress but is not induced by other stressors. Using Pgpdh-1::GFP expression as a phenotype, we screened Ϸ16,000 genes by RNAi feeding and identified 122 that cause constitutive activation of gpdh-1 expression and glycerol accumulation. Many of these genes function to regulate protein translation and cotranslational protein folding and to target and degrade denatured proteins, suggesting that the accumulation of misfolded proteins functions as a signal to activate osmoprotective gene expression and organic osmolyte accumulation in animal cells. Consistent with this hypothesis, 73% of these protein-homeostasis genes have been shown to slow age-dependent protein aggregation in C. elegans. Because diverse environmental stressors and numerous disease states result in protein misfolding, mechanisms must exist that discriminate between osmotically induced and other forms of stress-induced protein damage. Our findings provide a foundation for understanding how these damage-selectivity mechanisms function.Caenorhabditis elegans ͉ functional genomics ͉ organic osmolytes ͉ osmotic stress

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“…Unlike other chaperones linked to protein aggregation, the major cellular function of TRiC is to assist folding of newly translated polypeptides, rather than rescue stress-denatured proteins 19 . Therefore, the chaperonin is transcriptionally and functionally linked to protein synthesis and is not induced by stress 19 . Intriguingly, TRiC cooperates with Hsp70 during de novo folding of several proteins 2,10 .…”

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confidence: 99%

The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions

et al. 2006

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Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders 1 . Here, we show that the heterooligomeric chaperonin TRiC (also known as CCT) physically interacts with polyglutamine-expanded variants of huntingtin (Htt) and effectively inhibits their aggregation. Depletion of TRiC enhances polyglutamine aggregation in yeast and mammalian cells. Conversely, overexpression of a single TRiC subunit, CCT1, is sufficient to remodel Htt-aggregate morphology in vivo and in vitro, and reduces Htt-induced toxicity in neuronal cells. Because TRiC acts during de novo protein biogenesis 2 , this chaperonin may have an early role preventing Htt access to pathogenic conformations. Based on the specificity of the Htt-CCT1 interaction, the CCT1 substrate-binding domain may provide a versatile scaffold for therapeutic inhibitors of neurodegenerative disease.Late-onset neurodegenerative diseases are often associated with the accumulation of insoluble amyloid aggregates in neurons 3 . In many cases, such as spinocerebellar ataxia and Huntington's disease, aggregation is associated with expanded polyglutamine (polyQ) tracts in the disease gene, usually beyond a critical threshold of approximately 40 glutamine repeats 1 . Because polyQ disease proteins are the main aggregate component in affected neurons 4 , and glutamine tract length correlates with both aggregation propensity and age of onset of disease, it seems that toxic conformations of the polyQ-expanded proteins are directly responsible for neuronal dysfunction and death 1,5 .Recent studies suggest that the age-dependent accumulation of protein aggregates in neurodegenerative diseases reflects the progressive inability of the cellular quality control machinery to recognize and eliminate potentially toxic conformations. Molecular chaperones, which selectively bind non-native proteins and facilitate their folding or degradation 6,7 , have been shown to modulate aggregation and toxicity in neurodegenerative disease models. In particular, overexpression studies have demonstrated that the chaperone Hsp70 and its cofactors, such as Hsp40, can remodel polyQ aggregates and alleviate the toxicity of polyQ aggregation 4 . Although these studies establish a role for chaperones in modulating polyQ aggregation, the chaperones that normally interact with pathogenic polyQ conformations and 3Correspondence should be addressed to J.F. (jfrydman@stanford.edu).

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Systems Analyses Reveal Two Chaperone Networks with Distinct Functions in Eukaryotic Cells

Cited by 232 publications

References 60 publications

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression

The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions

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