Prion-Associated Toxicity is Rescued by Elimination of Cotranslational Chaperones

Keefer, Kathryn M.; True, Heather L.

doi:10.1371/journal.pgen.1006431

Cited by 10 publications

(16 citation statements)

References 53 publications

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“…B). We previously reported this phenomenon in the context of chaperone balance and concluded that the relative availability of the Hsp70s is a factor that influences toxicity (Keefer and True, ). However, we further demonstrated that imbalances can occur without changes in chaperone expression level.…”

Section: Resultsmentioning

confidence: 85%

“…In our lab strains, Ssa1 overexpression was not toxic in [ PSI +] cells without the concurrent overproduction of the prion‐forming protein Sup35 (Keefer and True, ). The Sup35 overexpression toxicity is known to be caused by the sequestration of translation termination factors (Vishveshwara et al ., ); however, the exacerbation of the toxicity by Ssa1 was a surprising result.…”

Section: Discussionmentioning

confidence: 90%

“…In our previous study, we investigated a system that mimicked Ssa1 overexpression, via increased availability of Ssa1 relative to Ssb1, without any change in expression of either Hsp70 (Keefer and True, ). Others have also reported that expression levels are less important than the interaction, or competition, between the Hsp70s (Kiktev et al ., ).…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that the levels of Hsp70s, namely Ssa1 and Ssb1, are at a fine balance in the yeast S. cerevisiae (Keefer and True, ). When more Ssa1 is available relative to Ssb1, [ PSI +] yeast experience exacerbated toxicity when Sup35 is concurrently overproduced.…”

Section: Introductionmentioning

confidence: 99%

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A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors

Keefer

True

2017

Molecular Microbiology

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Summary Molecular chaperones are responsible for managing protein folding from translation through degradation. These crucial machines ensure that protein homeostasis is optimally maintained for cell health. However, “too much of a good thing” can be deadly, and the excess of chaperones can be toxic under certain cellular conditions. For example, overexpression of Ssa1, a yeast Hsp70, is toxic to cells in folding-challenged states such as [PSI+]. We discovered that overexpression of the nucleotide exchange factor Sse1 can partially alleviate this toxicity. We further argue that the basis of the toxicity is related to the availability of Hsp70 cofactors, such as Hsp40 J-proteins and nucleotide exchange factors. Ultimately, our work informs future studies about functional chaperone balance and cautions against therapeutic chaperone modifications without a thorough examination of cofactor relationships.

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors

Keefer

True

2017

Molecular Microbiology

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“…One of these systems is based on the nascent polypeptide-associated complex representing a highly conserved triad of proteins that bind near the ribosome exit tunnel. It was shown that deletion of subunits of this complex rescues toxicity associated with the strong [ PSI + ] prion, which can be explained by changes in chaperone balance and distribution, whereby the folding of the prion protein is improved and the prion is rendered nontoxic [ 37 ]. Another chaperone-assisted [ PSI + ] detoxification system is based on the Hsp40 Sis1 chaperone [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

The Pub1 and Upf1 Proteins Act in Concert to Protect Yeast from Toxicity of the [PSI+] Prion

Urakov

Mitkevich

Dergalev

et al. 2018

IJMS

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The [PSI+] nonsense-suppressor determinant of Saccharomyces cerevisiae is based on the formation of heritable amyloids of the Sup35 (eRF3) translation termination factor. [PSI+] amyloids have variants differing in amyloid structure and in the strength of the suppressor phenotype. The appearance of [PSI+], its propagation and manifestation depend primarily on chaperones. Besides chaperones, the Upf1/2/3, Siw14 and Arg82 proteins restrict [PSI+] formation, while Sla2 can prevent [PSI+] toxicity. Here, we identify two more non-chaperone proteins involved in [PSI+] detoxification. We show that simultaneous lack of the Pub1 and Upf1 proteins is lethal to cells harboring [PSI+] variants with a strong, but not with a weak, suppressor phenotype. This lethality is caused by excessive depletion of the Sup45 (eRF1) termination factor due to its sequestration into Sup35 polymers. We also show that Pub1 acts to restrict excessive Sup35 prion polymerization, while Upf1 interferes with Sup45 binding to Sup35 polymers. These data allow consideration of the Pub1 and Upf1 proteins as a novel [PSI+] detoxification system.

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Toxicity and infectivity: insights from de novo prion formation

et al. 2017

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Prions are infectious misfolded proteins that assemble into oligomers and large aggregates, and are associated with neurodegeneration. It is believed that the oligomers contribute to cytotoxicity, although genetic and environmental factors have also been shown to have additional roles. The study of the yeast prion [PSI ] has provided valuable insights into how prions form and why they are toxic. Our recent work suggests that SDS-resistant oligomers arise and remodel early during the prion formation process, and lysates containing these newly formed oligomers are infectious. Previous work shows that toxicity is associated with prion formation and this toxicity is exacerbated by deletion of the VPS5 gene. Here, we show that newly made oligomer formation and infectivity of vps5∆ lysates are similar to wild-type strains. However using green fluorescent protein fusions, we observe that the assembly of fluorescent cytoplasmic aggregates during prion formation is different in vps5∆ strains. Instead of large immobile aggregates, vps5∆ strains have an additional population of small mobile foci. We speculate that changes in the cellular milieu in vps5∆ strains may reduce the cell's ability to efficiently recruit and sequester newly formed prion particles into central deposition sites, resulting in toxicity.

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Prion-Associated Toxicity is Rescued by Elimination of Cotranslational Chaperones

Cited by 10 publications

References 53 publications

A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors

A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors

The Pub1 and Upf1 Proteins Act in Concert to Protect Yeast from Toxicity of the [PSI+] Prion

Toxicity and infectivity: insights from de novo prion formation

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