The actin cytoskeletal network plays a role in yeast prion transmission and contributes to prion stability

Dorweiler, Jane E.; Oddo, Mitchell J.; Lyke, Douglas R.; Reilly, Jacob A.; Wisniewski, Brett T.; Davis, Emily E; Kuborn, Abigail M.; Merrill, Stephen J.; Manogaran, Anita L.

doi:10.1111/mmi.14528

Cited by 10 publications

(14 citation statements)

References 67 publications

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“…This shows that [ PSI + ] is being cured by asymmetric segregation. Aggregation of [ PIN + ] seeds was also observed by the Manogaran laboratory, who found that this occurred upon disruption of the actin cytoskeleton with a specific [ PIN + ] variant [ 44 ]. Imaging showed that this causes the appearance of larger [ PIN + ] aggregates, suggesting that curing was due to asymmetric segregation of the prion seeds.…”

Section: Curing By Asymmetric Segregationmentioning

confidence: 79%

Mechanisms for Curing Yeast Prions

Greene

Saba

Silberman

et al. 2020

IJMS

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Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing.

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Section: Curing By Asymmetric Segregationmentioning

confidence: 79%

Mechanisms for Curing Yeast Prions

Greene

Saba

Silberman

et al. 2020

IJMS

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“…Therefore, we used a genetic approach to understand the link between prion formation and actin networks, by using several actin point mutants. We used four previously characterized actin mutants [ 31 , 32 ] that show actin patch polarization defects ( act1-120 , act1-122) , actin cable defects ( act1-101 ), and a double point mutant that alters nucleotide binding ( act1-129 : R177A and D179A). It should be noted that another study showed that the single R177A mutation limits aggregate formation [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

Implications of the Actin Cytoskeleton on the Multi-Step Process of [PSI+] Prion Formation

Dorweiler

Lyke

Lemoine

et al. 2022

Viruses

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Yeast prions are self-perpetuating misfolded proteins that are infectious. In yeast, [PSI+] is the prion form of the Sup35 protein. While the study of [PSI+] has revealed important cellular mechanisms that contribute to prion propagation, the underlying cellular factors that influence prion formation are not well understood. Prion formation has been described as a multi-step process involving both the initial nucleation and growth of aggregates, followed by the subsequent transmission of prion particles to daughter cells. Prior evidence suggests that actin plays a role in this multi-step process, but actin’s precise role is unclear. Here, we investigate how actin influences the cell’s ability to manage newly formed visible aggregates and how actin influences the transmission of newly formed aggregates to future generations. At early steps, using 3D time-lapse microscopy, several actin mutants, and Markov modeling, we find that the movement of newly formed aggregates is random and actin independent. At later steps, our prion induction studies provide evidence that the transmission of newly formed prion particles to daughter cells is limited by the actin cytoskeletal network. We suspect that this limitation is because actin is used to possibly retain prion particles in the mother cell.

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“…Such a high prevalence might demonstrate the importance of the host-actin network in the cellular propagation of misfolded proteins. Indeed, actin has been shown to influence prion propagation in yeast (Dorweiler et al, 2020) and might be applicable as well in mammalian cells (See et al, 2021; Victoria and Zurzolo, 2017). Based on our data, the actin network might be a worthwhile target to further investigate.…”

Section: Discussionmentioning

confidence: 99%

An Arrayed Genome-Wide Perturbation Screen Identifies the Ribonucleoprotein hnRNP K As Rate-Limiting for Prion Propagation

Avar

Heinzer

Thackray

et al. 2022

Preprint

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A defining characteristic of mammalian prions is their capacity for self-sustained propagation. Theoretical considerations and experimental evidence suggest that prion propagation is modulated by cell-autonomous and non-autonomous modifiers. Using a novel quantitative phospholipase protection assay (QUIPPER) for high-throughput prion measurements, we performed an arrayed genome-wide RNA interference (RNAi) screen aimed at detecting modifiers of prion propagation. We exposed prion-infected cells in high-density microplates to 35’364 ternary pools of 52’746 siRNAs targeting 17’582 genes representing the mouse protein-coding transcriptome. We identified 1191 modulators of prion propagation. While 1151 of these modified the expression of both the pathological prion protein, PrPSc, and its cellular counterpart PrPC, 40 genes affected selectively PrPSc. Of the latter, 20 genes augmented prion production when suppressed. A prominent limiter of prion propagation was the heterogeneous nuclear ribonucleoprotein Hnrnpk. Psammaplysene A (PSA), which binds Hnrnpk, reduced prion levels in cultured cells and protected them from cytotoxicity. PSA also reduced prion levels in infected cerebellar organotypic slices and alleviated locomotor deficits in prion-infected Drosophila melanogaster expressing ovine PrPC. Hence, genome-wide QUIPPER-based perturbations can discover actionable cellular pathways involved in prion propagation. Finally, the unexpected identification of a prioncontrolling ribonucleoprotein suggests a role for RNA in the generation of infectious prions.

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The actin cytoskeletal network plays a role in yeast prion transmission and contributes to prion stability

Cited by 10 publications

References 67 publications

Mechanisms for Curing Yeast Prions

Mechanisms for Curing Yeast Prions

Implications of the Actin Cytoskeleton on the Multi-Step Process of [PSI+] Prion Formation

An Arrayed Genome-Wide Perturbation Screen Identifies the Ribonucleoprotein hnRNP K As Rate-Limiting for Prion Propagation

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