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18 pages, 36758 KiB

Open AccessArticle

Prion-Dependent Lethality of sup35 Missense Mutations Is Caused by Low GTPase Activity of the Mutant eRF3 Protein

by Nina P. Trubitsina, Olga M. Zemlyanko, Andrew G. Matveenko, Stanislav A. Bondarev, Svetlana E. Moskalenko, Evgeniia M. Maksiutenko, Anna A. Zudilova, Tatiana M. Rogoza and Galina A. Zhouravleva

Int. J. Mol. Sci. 2025, 26(7), 3434; https://doi.org/10.3390/ijms26073434 - 6 Apr 2025

Viewed by 626

Abstract

The essential SUP35 gene encodes yeast translation termination factor Sup35/eRF3. The N-terminal domain of Sup35 is also responsible for Sup35 prionization that leads to generation of the [PSI⁺] prion. Previously we isolated different types of sup35 mutations (missense and nonsense) [...] Read more.

The essential SUP35 gene encodes yeast translation termination factor Sup35/eRF3. The N-terminal domain of Sup35 is also responsible for Sup35 prionization that leads to generation of the [PSI⁺] prion. Previously we isolated different types of sup35 mutations (missense and nonsense) and demonstrated that sup35 nonsense mutations (sup35-n) are incompatible with the [PSI⁺] prion, leading to lethality of sup35-n [PSI⁺] haploid cells. Here, we show that sup35 missense mutations (sup35-m) within conservative regions of the Sup35 C-domain result in lethality of [PSI⁺] cells because of weak activity of Sup35/eRF3 as a translation termination factor. Mutant Sup35 maintain their ability to be incorporated into pre-existing [PSI⁺] aggregates and to form amyloid aggregates in vitro, while sup35-m mutations do not influence the [PSI⁺] prion induction and stability. All these mutations (D363N, R372K, T378I) are located in the conservative GTPase region of Sup35, decreasing the GTPase activity of mutated proteins. We propose that such low activity of mutant Sup35 combined with aggregation of Sup35 constituting the [PSI⁺] prion is not sufficient to maintain the viability of yeast cells. Full article

(This article belongs to the Special Issue Yeast: Molecular and Cell Biology)

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20 pages, 2246 KiB

Open AccessArticle

On the Significance of the Terminal Location of Prion-Forming Regions of Yeast Proteins

by Arthur A. Galliamov, Valery N. Urakov, Alexander A. Dergalev and Vitaly V. Kushnirov

Int. J. Mol. Sci. 2025, 26(4), 1637; https://doi.org/10.3390/ijms26041637 - 14 Feb 2025

Viewed by 741

Abstract

The prion-forming regions (PFRs) of yeast prion proteins are usually located at either the N- or C-terminus of a protein. In the Sup35 prion, the main prion structure contains 71 N-terminal residues. Here, we investigated the importance of the terminal PFR location for [...] Read more.

The prion-forming regions (PFRs) of yeast prion proteins are usually located at either the N- or C-terminus of a protein. In the Sup35 prion, the main prion structure contains 71 N-terminal residues. Here, we investigated the importance of the terminal PFR location for prion properties. Two prionogenic sequences of 29 and 30 residues and two random sequences of 23 and 15 residues were added to the Sup35 N-terminus, making the original PFR internal. These proteins were overproduced in yeast with two variants of the Sup35 prion. Mapping of the prion-like structures of these proteins by partial proteinase K digestion showed that in most cases, the extensions acquired an amyloid fold, and, strikingly, the prion structure was no longer present or was substantially altered at its original location. The addition of two to five residues to the Sup35 N-terminus often resulted in prion instability and loss when the respective genes were used to replace chromosomal SUP35. The structures of yeast prions Mot3, Swi1, Lsb2, candidate prions Asm4, Nsp1, Cbk1, Cpp1, and prions based on scrambled Sup35 PFRs were mapped. The mapping showed that the N-terminal location of a QN-rich sequence predisposes to, but does not guarantee, the formation of a prion structure by it and that the prion structure located near a terminus does not always include the actual terminus, as in the cases of Sup35 and Rnq1. Full article

(This article belongs to the Section Molecular Microbiology)

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21 pages, 3047 KiB

Open AccessArticle

Prion-like Properties of Short Isoforms of Human Chromatin Modifier PHC3

by Daniil Kachkin, Andrew A. Zelinsky, Nina V. Romanova, Konstantin Y. Kulichikhin, Pavel A. Zykin, Julia I. Khorolskaya, Zachery J. Deckner, Andrey V. Kajava, Aleksandr A. Rubel and Yury O. Chernoff

Int. J. Mol. Sci. 2025, 26(4), 1512; https://doi.org/10.3390/ijms26041512 - 11 Feb 2025

Viewed by 2744

Abstract

The formation of self-perpetuating protein aggregates such as amyloids is associated with various diseases and provides a basis for transmissible (infectious or heritable) protein isoforms (prions). Many human proteins involved in the regulation of transcription contain potentially amyloidogenic regions. Here, it is shown [...] Read more.

The formation of self-perpetuating protein aggregates such as amyloids is associated with various diseases and provides a basis for transmissible (infectious or heritable) protein isoforms (prions). Many human proteins involved in the regulation of transcription contain potentially amyloidogenic regions. Here, it is shown that short N-terminal isoforms of the human protein PHC3, a component of the chromatin-modifying complex PRC1 (Polycomb repressive complex 1), can form prion-like aggregates in yeast assays, exhibit amyloid properties in the E. coli-based C-DAG assay, and produce detergent-resistant aggregates when ectopically expressed in cultured human cells. Moreover, aggregates of short isoforms can sequester the full-length PHC3 protein, causing its accumulation in the cytosol instead of the nucleus. The introduction of an aggregating short PHC3 isoform alters the transcriptional profile of cultured human cells. It is proposed that the aggregation of short isoforms is involved in the feedback downregulation of PRC1 activity, leading to more open chromatin configuration. Full article

(This article belongs to the Collection Feature Papers in Molecular Microbiology)

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18 pages, 3725 KiB

Open AccessArticle

Potential of Marine Sponge Metabolites against Prions: Bromotyrosine Derivatives, a Family of Interest

by Maha Sinane, Colin Grunberger, Lucile Gentile, Céline Moriou, Victorien Chaker, Pierre Coutrot, Alain Guenneguez, Marie-Aude Poullaouec, Solène Connan, Valérie Stiger-Pouvreau, Mayalen Zubia, Yannick Fleury, Stéphane Cérantola, Nelly Kervarec, Ali Al-Mourabit, Sylvain Petek and Cécile Voisset

Mar. Drugs 2024, 22(10), 456; https://doi.org/10.3390/md22100456 - 4 Oct 2024

Viewed by 2159

Abstract

The screening of 166 extracts from tropical marine organisms (invertebrates, macroalgae) and 3 cyclolipopeptides from microorganisms against yeast prions highlighted the potential of Verongiida sponges to prevent the propagation of prions. We isolated the known compounds purealidin Q (1), aplysamine-2 ( [...] Read more.

The screening of 166 extracts from tropical marine organisms (invertebrates, macroalgae) and 3 cyclolipopeptides from microorganisms against yeast prions highlighted the potential of Verongiida sponges to prevent the propagation of prions. We isolated the known compounds purealidin Q (1), aplysamine-2 (2), pseudoceratinine A (3), aerophobin-2 (4), aplysamine-1 (5), and pseudoceratinine B (6) for the first time from the Wallisian sponge Suberea laboutei. We then tested compounds 1–6 and sixteen other bromotyrosine and bromophenol derivatives previously isolated from Verongiida sponges against yeast prions, demonstrating the potential of 1–3, 5, 6, aplyzanzine C (7), purealidin A (10), psammaplysenes D (11) and F (12), anomoian F (14), and N,N-dimethyldibromotyramine (15). Following biological tests on mammalian cells, we report here the identification of the hitherto unknown ability of the six bromotyrosine derivatives 1, 2, 5, 7, 11, and 14 of marine origin to reduce the spread of the PrP^Sc prion and the ability of compounds 1 and 2 to reduce endoplasmic reticulum stress. These two biological activities of these bromotyrosine derivatives are, to our knowledge, described here for the first time, offering a new therapeutic perspective for patients suffering from prion diseases that are presently untreatable and consequently fatal. Full article

(This article belongs to the Section Marine Pharmacology)

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14 pages, 1503 KiB

Open AccessArticle

Modelling Yeast Prion Dynamics: A Fractional Order Approach with Predictor–Corrector Algorithm

by Daasara Keshavamurthy Archana, Doddabhadrappla Gowda Prakasha and Nasser Bin Turki

Fractal Fract. 2024, 8(9), 542; https://doi.org/10.3390/fractalfract8090542 - 19 Sep 2024

Cited by 2 | Viewed by 796

Abstract

This work aims to comprehend the dynamics of neurodegenerative disease using a mathematical model of fractional-order yeast prions. In the context of the Caputo fractional derivative, we here study and examine the solution of this model using the Predictor–Corrector approach. An analysis has [...] Read more.

This work aims to comprehend the dynamics of neurodegenerative disease using a mathematical model of fractional-order yeast prions. In the context of the Caputo fractional derivative, we here study and examine the solution of this model using the Predictor–Corrector approach. An analysis has been conducted on the existence and uniqueness of the selected model. Also, we examined the model’s stability and the existence of equilibrium points. With the purpose of analyzing the dynamics of the Sup35 monomer and Sup35 prion population, we displayed the graphs to show the obtained solutions over time. Graphical simulations show that the behaviour of the populations can change based on fractional orders and threshold parameter values. This work may present a good example of how biological theories and data can be better understood via mathematical modelling. Full article

(This article belongs to the Special Issue Recent Advances in Fractional Differential Equations and Their Applications, 2nd Edition)

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5 pages, 163 KiB

Open AccessEditorial

Exploring Fundamentals of Prion Biology Using Natural Yeast Prions and Mammalian PrP

by Irina L. Derkatch and Susan W. Liebman

Viruses 2024, 16(5), 790; https://doi.org/10.3390/v16050790 - 16 May 2024

Viewed by 1651

Abstract

The key postulate of the prion paradigm is that some proteins can take on unconventional conformations and pass these conformations to newly synthesized protein molecules with the same primary structure [...] Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

15 pages, 2104 KiB

Open AccessArticle

Mapping of Prion Structures in the Yeast Rnq1

by Arthur A. Galliamov, Alena D. Malukhina and Vitaly V. Kushnirov

Int. J. Mol. Sci. 2024, 25(6), 3397; https://doi.org/10.3390/ijms25063397 - 17 Mar 2024

Cited by 1 | Viewed by 1712

Abstract

The Rnq1 protein is one of the best-studied yeast prions. It has a large potentially prionogenic C-terminal region of about 250 residues. However, a previous study indicated that only 40 C-terminal residues form a prion structure. Here, we mapped the actual and potential [...] Read more.

The Rnq1 protein is one of the best-studied yeast prions. It has a large potentially prionogenic C-terminal region of about 250 residues. However, a previous study indicated that only 40 C-terminal residues form a prion structure. Here, we mapped the actual and potential prion structures formed by Rnq1 and its variants truncated from the C-terminus in two [RNQ+] strains using partial proteinase K digestion. The location of these structures differed in most cases from previous predictions by several computer algorithms. Some aggregation patterns observed microscopically for the Rnq1 hybrid proteins differed significantly from those previously observed for Sup35 prion aggregates. The transfer of a prion from the full-sized Rnq1 to its truncated versions caused substantial alteration of prion structures. In contrast to the Sup35 and Swi1, the terminal prionogenic region of 72 residues was not able to efficiently co-aggregate with the full-sized Rnq1 prion. GFP fusion to the Rnq1 C-terminus blocked formation of the prion structure at the Rnq1 C-terminus. Thus, the Rnq1-GFP fusion mostly used in previous studies cannot be considered a faithful tool for studying Rnq1 prion properties. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)

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17 pages, 2229 KiB

Open AccessEditor’s ChoiceArticle

The Properties and Domain Requirements for Phase Separation of the Sup35 Prion Protein In Vivo

by Bryan Grimes, Walter Jacob, Amanda R. Liberman, Nathan Kim, Xiaohong Zhao, Daniel C. Masison and Lois E. Greene

Biomolecules 2023, 13(9), 1370; https://doi.org/10.3390/biom13091370 - 10 Sep 2023

Cited by 10 | Viewed by 2809

Abstract

The Sup35 prion protein of budding yeast has been reported to undergo phase separation to form liquid droplets both at low pH in vitro and when energy depletion decreases the intracellular pH in vivo. It also has been shown using purified proteins that [...] Read more.

The Sup35 prion protein of budding yeast has been reported to undergo phase separation to form liquid droplets both at low pH in vitro and when energy depletion decreases the intracellular pH in vivo. It also has been shown using purified proteins that this phase separation is driven by the prion domain of Sup35 and does not re-quire its C-terminal domain. In contrast, we now find that a Sup35 fragment consisting of only the N-terminal prion domain and the M-domain does not phase separate in vivo; this phase separation of Sup35 requires the C-terminal domain, which binds Sup45 to form the translation termination complex. The phase-separated Sup35 not only colocalizes with Sup45 but also with Pub1, a stress granule marker protein. In addition, like stress granules, phase separation of Sup35 appears to require mRNA since cycloheximide treatment, which inhibits mRNA release from ribosomes, prevents phase separation of Sup35. Finally, unlike Sup35 in vitro, Sup35 condensates do not disassemble in vivo when the intracellular pH is increased. These results suggest that, in energy-depleted cells, Sup35 forms supramolecular assemblies that differ from the Sup35 liquid droplets that form in vitro. Full article

(This article belongs to the Section Molecular Structure and Dynamics)

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16 pages, 446 KiB

Open AccessReview

How Big Is the Yeast Prion Universe?

by Galina A. Zhouravleva, Stanislav A. Bondarev and Nina P. Trubitsina

Int. J. Mol. Sci. 2023, 24(14), 11651; https://doi.org/10.3390/ijms241411651 - 19 Jul 2023

Cited by 5 | Viewed by 2426

Abstract

The number of yeast prions and prion-like proteins described since 1994 has grown from two to nearly twenty. If in the early years most scientists working with the classic mammalian prion, PrP^Sc, were skeptical about the possibility of using the term [...] Read more.

The number of yeast prions and prion-like proteins described since 1994 has grown from two to nearly twenty. If in the early years most scientists working with the classic mammalian prion, PrP^Sc, were skeptical about the possibility of using the term prion to refer to yeast cytoplasmic elements with unusual properties, it is now clear that prion-like phenomena are widespread and that yeast can serve as a convenient model for studying them. Here we give a brief overview of the yeast prions discovered so far and focus our attention to the various approaches used to identify them. The prospects for the discovery of new yeast prions are also discussed. Full article

(This article belongs to the Special Issue Yeast: Molecular and Cell Biology)

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18 pages, 2479 KiB

Open AccessArticle

Overexpression of Hsp104 by Causing Dissolution of the Prion Seeds Cures the Yeast [PSI⁺] Prion

by Katherine E. Stanford, Xiaohong Zhao, Nathan Kim, Daniel C. Masison and Lois E. Greene

Int. J. Mol. Sci. 2023, 24(13), 10833; https://doi.org/10.3390/ijms241310833 - 29 Jun 2023

Cited by 2 | Viewed by 1882

Abstract

The yeast Sup35 protein misfolds into the infectious [PSI⁺] prion, which is then propagated by the severing activity of the molecular chaperone, Hsp104. Unlike other yeast prions, this prion is unique in that it is efficiently cured by the overexpression [...] Read more.

The yeast Sup35 protein misfolds into the infectious [PSI⁺] prion, which is then propagated by the severing activity of the molecular chaperone, Hsp104. Unlike other yeast prions, this prion is unique in that it is efficiently cured by the overexpression as well as the inactivation of Hsp104. However, it is controversial whether curing by overexpression is due to the dissolution of the prion seeds by the trimming activity of Hsp104 or the asymmetric segregation of the prion seeds between mother and daughter cells which requires cell division. To answer this question, we conducted experiments and found no difference in the extent of curing between mother and daughter cells when half of the cells were cured by Hsp104 overexpression in one generation. Furthermore, curing was not affected by the lack of Sir2 expression, which was reported to be required for asymmetric segregation of the [PSI⁺] seeds. More importantly, when either hydroxyurea or ethanol were used to inhibit cell division, the extent of curing by Hsp104 overexpression was not significantly reduced. Therefore, the curing of [PSI⁺] by Hsp104 overexpression is not due to asymmetric segregation of the prion seeds, but rather their dissolution by Hsp104. Full article

(This article belongs to the Special Issue Yeast as a Model System to Study Human Diseases)

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27 pages, 6584 KiB

Open AccessArticle

Yeast Chaperone Hsp70-Ssb Modulates a Variety of Protein-Based Heritable Elements

by Lina M. Jay-Garcia, Joseph L. Cornell, Rebecca L. Howie, Quincy L. Faber, Abigail Salas, Tatiana A. Chernova and Yury O. Chernoff

Int. J. Mol. Sci. 2023, 24(10), 8660; https://doi.org/10.3390/ijms24108660 - 12 May 2023

Cited by 3 | Viewed by 2275

Abstract

Prions are transmissible self-perpetuating protein isoforms associated with diseases and heritable traits. Yeast prions and non-transmissible protein aggregates (mnemons) are frequently based on cross-β ordered fibrous aggregates (amyloids). The formation and propagation of yeast prions are controlled by chaperone machinery. Ribosome-associated chaperone Hsp70-Ssb [...] Read more.

Prions are transmissible self-perpetuating protein isoforms associated with diseases and heritable traits. Yeast prions and non-transmissible protein aggregates (mnemons) are frequently based on cross-β ordered fibrous aggregates (amyloids). The formation and propagation of yeast prions are controlled by chaperone machinery. Ribosome-associated chaperone Hsp70-Ssb is known (and confirmed here) to modulate formation and propagation of the prion form of the Sup35 protein [PSI⁺]. Our new data show that both formation and mitotic transmission of the stress-inducible prion form of the Lsb2 protein ([LSB⁺]) are also significantly increased in the absence of Ssb. Notably, heat stress leads to a massive accumulation of [LSB⁺] cells in the absence of Ssb, implicating Ssb as a major downregulator of the [LSB⁺]-dependent memory of stress. Moreover, the aggregated form of Gγ subunit Ste18, [STE⁺], behaving as a non-heritable mnemon in the wild-type strain, is generated more efficiently and becomes heritable in the absence of Ssb. Lack of Ssb also facilitates mitotic transmission, while lack of the Ssb cochaperone Hsp40-Zuo1 facilitates both spontaneous formation and mitotic transmission of the Ure2 prion, [URE3]. These results demonstrate that Ssb is a general modulator of cytosolic amyloid aggregation, whose effect is not restricted only to [PSI⁺]. Full article

(This article belongs to the Collection Feature Papers in Molecular Microbiology)

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18 pages, 5492 KiB

Open AccessReview

Disassembly of Amyloid Fibril with Infrared Free Electron Laser

by Takayasu Kawasaki, Koichi Tsukiyama and Phuong H. Nguyen

Int. J. Mol. Sci. 2023, 24(4), 3686; https://doi.org/10.3390/ijms24043686 - 12 Feb 2023

Cited by 3 | Viewed by 3040

Abstract

Amyloid fibril causes serious amyloidosis such as neurodegenerative diseases. The structure is composed of rigid β-sheet stacking conformation which makes it hard to disassemble the fibril state without denaturants. Infrared free electron laser (IR-FEL) is an intense picosecond pulsed laser that is oscillated [...] Read more.

Amyloid fibril causes serious amyloidosis such as neurodegenerative diseases. The structure is composed of rigid β-sheet stacking conformation which makes it hard to disassemble the fibril state without denaturants. Infrared free electron laser (IR-FEL) is an intense picosecond pulsed laser that is oscillated through a linear accelerator, and the oscillation wavelengths are tunable from 3 μm to 100 μm. Many biological and organic compounds can be structurally altered by the mode-selective vibrational excitations due to the wavelength variability and the high-power oscillation energy (10–50 mJ/cm²). We have found that several different kinds of amyloid fibrils in amino acid sequences were commonly disassembled by the irradiation tuned to amide I (6.1–6.2 μm) where the abundance of β-sheet decreased while that of α-helix increased by the vibrational excitation of amide bonds. In this review, we would like to introduce the IR-FEL oscillation system briefly and describe combination studies of experiments and molecular dynamics simulations on disassembling amyloid fibrils of a short peptide (GNNQQNY) from yeast prion and 11-residue peptide (NFLNCYVSGFH) from β2-microglobulin as representative models. Finally, possible applications of IR-FEL for amyloid research can be proposed as a future outlook. Full article

(This article belongs to the Special Issue Structure and Formation Mechanism of Amyloid Fibrils)

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18 pages, 2451 KiB

Open AccessArticle

Methionine Sulfoxide Reductases Suppress the Formation of the [PSI⁺] Prion and Protein Aggregation in Yeast

by Jana Schepers, Zorana Carter, Paraskevi Kritsiligkou and Chris M. Grant

Antioxidants 2023, 12(2), 401; https://doi.org/10.3390/antiox12020401 - 7 Feb 2023

Cited by 2 | Viewed by 2364

Abstract

Prions are self-propagating, misfolded forms of proteins associated with various neurodegenerative diseases in mammals and heritable traits in yeast. How prions form spontaneously into infectious amyloid-like structures without underlying genetic changes is poorly understood. Previous studies have suggested that methionine oxidation may underlie [...] Read more.

Prions are self-propagating, misfolded forms of proteins associated with various neurodegenerative diseases in mammals and heritable traits in yeast. How prions form spontaneously into infectious amyloid-like structures without underlying genetic changes is poorly understood. Previous studies have suggested that methionine oxidation may underlie the switch from a soluble protein to the prion form. In this current study, we have examined the role of methionine sulfoxide reductases (MXRs) in protecting against de novo formation of the yeast [PSI⁺] prion, which is the amyloid form of the Sup35 translation termination factor. We show that [PSI⁺] formation is increased during normal and oxidative stress conditions in mutants lacking either one of the yeast MXRs (Mxr1, Mxr2), which protect against methionine oxidation by reducing the two epimers of methionine-S-sulfoxide. We have identified a methionine residue (Met124) in Sup35 that is important for prion formation, confirming that direct Sup35 oxidation causes [PSI⁺] prion formation. [PSI⁺] formation was less pronounced in mutants simultaneously lacking both MXR isoenzymes, and we show that the morphology and biophysical properties of protein aggregates are altered in this mutant. Taken together, our data indicate that methionine oxidation triggers spontaneous [PSI⁺] prion formation, which can be alleviated by methionine sulfoxide reductases. Full article

(This article belongs to the Special Issue Role of Methionine Oxidation in the Progression of Oxidative Stress and Age-Related Diseases)

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11 pages, 2720 KiB

Open AccessArticle

Septin Defects Favour Symmetric Inheritance of the Budding Yeast Deceptive Courtship Memory

by Fozia Akhtar, Bastien Brignola and Fabrice Caudron

Int. J. Mol. Sci. 2023, 24(3), 3003; https://doi.org/10.3390/ijms24033003 - 3 Feb 2023

Cited by 1 | Viewed by 1846

Abstract

Mnemons are prion-like elements that encode cellular memories of past cellular adaptations and do not spread to progenies during cell divisions. During the deceptive courtship in budding yeast, the Whi3 mnemon (Whi3^mnem) condenses into a super-assembly to encode a mating pheromone [...] Read more.

Mnemons are prion-like elements that encode cellular memories of past cellular adaptations and do not spread to progenies during cell divisions. During the deceptive courtship in budding yeast, the Whi3 mnemon (Whi3^mnem) condenses into a super-assembly to encode a mating pheromone refractory state established in the mother cell. Whi3^mnem is confined to the mother cell such that their daughter cells have the ability to respond to the mating pheromone. Confinement of Whi3^mnem involves its association with the endoplasmic reticulum membranes and the compartmentalization of these membranes by the lateral membrane diffusion barrier at the bud neck, the limit between the mother cell and the bud. However, during the first cell division after the establishment of the pheromone refractory state, this adaptation is more likely to be inherited by the daughter cell than in subsequent cell divisions. Here, we show that the first cell division is associated with larger daughter cells and cytokinesis defects, traits that are not observed in subsequent cell divisions. The cytoskeletal septin protein shows aberrant localisation in these divisions and the septin-dependent endoplasmic reticulum membrane diffusion barrier is weakened. Overall, these data suggest that cytokinesis defects associated with prolonged cell division can alter the confinement and inheritance pattern of a cellular memory. Full article

(This article belongs to the Special Issue Protein-Based Infection, Inheritance, and Memory)

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17 pages, 2789 KiB

Open AccessArticle

Human J-Domain Protein DnaJB6 Protects Yeast from [PSI⁺] Prion Toxicity

by Richard E. Dolder, Jyotsna Kumar, Michael Reidy and Daniel C. Masison

Biology 2022, 11(12), 1846; https://doi.org/10.3390/biology11121846 - 18 Dec 2022

Cited by 2 | Viewed by 2905

Abstract

Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington’s, Alzheimer’s, and Parkinson’s diseases, respectively. In yeast, amyloid-based [PSI⁺] prions, which rely on [...] Read more.

Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington’s, Alzheimer’s, and Parkinson’s diseases, respectively. In yeast, amyloid-based [PSI⁺] prions, which rely on the related JDP Sis1 for replication, have a latent toxicity that is exposed by reducing Sis1 function. Anti-amyloid activity of DnaJB6 is very effective against weak [PSI⁺] prions and the Sup35 amyloid that composes them, but ineffective against strong [PSI⁺] prions composed of structurally different amyloid of the same Sup35. This difference reveals limitations of DnaJB6 that have implications regarding its therapeutic use for amyloid disease. Here, we find that when Sis1 function is reduced, DnaJB6 represses toxicity of strong [PSI⁺] prions and inhibits their propagation. Both Sis1 and DnaJB6, which are regulators of protein chaperone Hsp70, counteract the toxicity by reducing excessive incorporation of the essential Sup35 into prion aggregates. However, while Sis1 apparently requires interaction with Hsp70 to detoxify [PSI⁺], DnaJB6 counteracts prion toxicity by a different, Hsp70-independent mechanism. Full article

(This article belongs to the Special Issue 10th Anniversary of Biology: Amyloid Interaction in Regulation of Protein Function, Prion Propagation, and Cell Death)

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