The [RNQ+] prion: A model of both functional and pathological amyloid

Stein, Kevin C.; True, Heather L.

doi:10.4161/pri.5.4.18213

Cited by 11 publications

(13 citation statements)

References 29 publications

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“…For example, endogenous prions, such as [ PIN + ] and/or [ PSI + ] (Gokhale et al ., ; Gong et al ., ; Kochneva‐Pervukhova et al ., ; Zhao et al ., ), promote aggregation and toxicity of expanded polyQ constructs in the yeast huntingtin model. Overproduction of Sup35 (Chernoff et al ., ; Derkatch et al ., ; Vishveshwara et al ., ) or Rnq1 (Douglas et al ., ; Stein & True, ; Treusch & Lindquist, ) is toxic to prion‐containing cells. At least in some cases, this toxicity is associated with the sequestration of prion‐interacting proteins.…”

Section: Prions and Adaptationmentioning

confidence: 99%

Physiological and environmental control of yeast prions

Chernova¹,

Wilkinson²,

Chernoff³

2014

FEMS Microbiol Rev

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Prions are self-perpetuating protein isoforms that cause fatal and incurable neurodegenerative disease in mammals. Recent evidence indicates that a majority of human proteins involved in amyloid and neural inclusion disorders possess at least some prion properties. In lower eukaryotes, such as yeast, prions act as epigenetic elements, which increase phenotypic diversity by altering a range of cellular processes. While some yeast prions are clearly pathogenic, it is also postulated that prion formation could be beneficial in variable environmental conditions. Yeast and mammalian prions have similar molecular properties. Crucial cellular factors and conditions influencing prion formation and propagation were uncovered in the yeast models. Stress-related chaperones, protein quality control deposits, degradation pathways and cytoskeletal networks control prion formation and propagation in yeast. Environmental stresses trigger prion formation and loss, supposedly acting via influencing intracellular concentrations of the prion-inducing proteins, and/or by localizing prionogenic proteins to the prion induction sites via heterologous ancillary helpers. Physiological and environmental modulation of yeast prions points to new opportunities for pharmacological intervention and/or prophylactic measures targeting general cellular systems rather than the properties of individual amyloids and prions.

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Section: Prions and Adaptationmentioning

confidence: 99%

Physiological and environmental control of yeast prions

Chernova¹,

Wilkinson²,

Chernoff³

2014

FEMS Microbiol Rev

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“…Cells harbouring stronger [ PSI +] variants cause more nonsense suppression (less faithful translation termination) as compared to cells propagating weaker [ PSI +] variants. The [ RNQ +] prion, on the other hand, is formed from the Rnq1 protein that has no clear function in its non‐prion form (Stein and True, ). However, [ RNQ +] is responsible for inducing the de novo formation of the [ PSI +] prion (Derkatch et al ., ; Osherovich and Weissman, ), and [ RNQ +] variants are distinguished based on how readily [ PSI +] forms in [ RNQ +] cells (Bradley et al ., ; Kalastavadi and True, ).…”

Section: Introductionmentioning

confidence: 99%

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Stein

True

2014

Molecular Microbiology

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Summary Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1, and its human ortholog Hdj1, had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation.

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“…Spontaneous formation of [ PSI + ] is dependent on the presence of the [ RNQ + ] prion (Stein and True, ). [ RNQ + ] is formed by ordered aggregation of Rnq1, a protein of unknown function (Sondheimer and Lindquist, ; Strawn and True, ).…”

Section: Introductionmentioning

confidence: 99%

“…Spontaneous formation of [PSI + ] is dependent on the presence of the [RNQ + ] prion (Stein and True, 2011).…”

Section: Introductionmentioning

confidence: 99%

Wild yeast harbour a variety of distinct amyloid structures with strong prion‐inducing capabilities

Westergard

True

2014

Molecular Microbiology

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Summary Variation in amyloid structures profoundly influences a wide array of pathological phenotypes in mammalian protein conformation disorders and dominantly inherited phenotypes in yeast. Here, we describe, for the first time, naturally occurring, self-propagating, structural variants of a prion protein isolated from wild strains of the yeast Saccharomyces cerevisiae. Variants of the [RNQ+] prion propagating in a variety of wild yeast differ biochemically, in their intracellular distributions, and in their ability to promote formation of the [PSI+] prion. [PSI+] is an epigenetic regulator of cellular phenotype and adaptability. Strikingly, we find that most natural [RNQ+] variants induced [PSI+] at high frequencies and the majority of [PSI+] variants elicited strong cellular phenotypes. We hypothesize that the presence of an efficient [RNQ+] template primes the cell for [PSI+] formation in order to induce [PSI+] in conditions where it would be advantageous. These studies utilize naturally occurring structural variants to expand our understanding of the consequences of diverse prion conformations on cellular phenotypes.

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The [RNQ+] prion: A model of both functional and pathological amyloid

Cited by 11 publications

References 29 publications

Physiological and environmental control of yeast prions

Physiological and environmental control of yeast prions

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Wild yeast harbour a variety of distinct amyloid structures with strong prion‐inducing capabilities

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