Hsp104-Dependent Remodeling of Prion Complexes Mediates Protein-Only Inheritance

Satpute-Krishnan, Prasanna; Langseth, Sara X; Serio, Tricia R.

doi:10.1371/journal.pbio.0050024

Cited by 130 publications

(201 citation statements)

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“…For these studies, we used a fluorescent reporter, which is expressed only upon read-through of an upstream stop codon (GST-UGA-DsRed-NLS; Satpute-Krishnan and Serio, 2005;Kawai-Noma et al, 2006). Expression of the red fluorescent protein in zygotes requires the rapid conversion of soluble, functional Sup35 to the aggregated state upon fusion of the mating partners (Satpute-Krishnan et al, 2007). Importantly, expression of this reporter was not affected by loss of NatA function independent of its effects on the [PSI ϩ ] phenotype (Supplemental Figure S7).…”

Section: Sup35 Efficiently Joins Prion Complexes In Thementioning

confidence: 99%

“…Fluorescence recovery after photobleaching (FRAP) analysis was performed and analyzed as previously described (Satpute-Krishnan et al, 2007), but in this case data were collected on a Zeiss LSM 510 confocal microscope.…”

Section: Imaging Digital Processing and Fluorescence Recovery Aftermentioning

confidence: 99%

“…In strains lacking NatA function, heritable Sup35 prion complexes are uncoupled from their phenotypic effects. In contrast to other known modulators of [PSI ϩ ] propagation that appear to act by altering prion complex dynamics (Jung et al, 2000;Wegrzyn et al, 2001;Kryndushkin et al, 2003;Song et al, 2005;Satpute-Krishnan et al, 2007), NatA null strains efficiently incorporate soluble Sup35 into existing prion complexes, but the nature of this interaction is altered, allowing faithful translation termination. …”

mentioning

confidence: 91%

“…First, they template the conversion of newly synthesized Sup35 protein to the prion form (Patino et al, 1996;Satpute-Krishnan and Serio, 2005). Second, they are continually regenerated to create new surfaces for efficient conversion (Ness et al, 2002;Cox et al, 2003;Satpute-Krishnan et al, 2007), and third, they are partitioned to daughter cells where they continue the cycle and allow inheritance of the associated phenotype (Cox et al, 2003;Satpute-Krishnan et al, 2007). Thus, the strong link between protein state and phenotype that allows proteins to act as epigenetic elements is established and maintained through a multistep pathway of protein dynamics (Pezza and Serio, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…To rule out this possibility, we monitored the mobility of Sup35-GFP in wild-type and NatA mutant strains using FRAP experiments, which are capable of quantitatively detecting soluble Sup35-GFP in individual cells containing a mixture of protein forms (Satpute-Krishnan et al, 2007). When a [psi Ϫ ] cell expressing Sup35-GFP is mated to an unmarked [psi Ϫ ] cell and the resulting zygote is analyzed by FRAP, fluorescence recovery in the bleached area is rapid, with a half-time (t 1/2 ) ϳ0.7 s. However, when the same Sup35-GFP expressing [psi Ϫ ] strain is mated to an unmarked wild-type [PSI ϩ ] strain, fluorescence recovery is slowed (t 1/2 ϳ3.1 s) because of the incorporation of soluble Sup35-GFP into prion complexes (Song et al, 2005;Satpute-Krishnan et al, 2007). When a [psi Ϫ ] strain expressing Sup35-GFP was mated to an unmarked NatA mutant [PSI ϩ ] strain, the rate of fluorescence recovery by FRAP was indistinguishable from the wild-type [psi Ϫ ] ϫ [PSI ϩ ] cross (t 1/2 ϳ2.7 s, Figure 5E), consistent with the rapid incorporation of soluble Sup35 in this cross ( Figure 5A).…”

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confidence: 99%

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The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

Pezza

Langseth

Yamamoto

et al. 2009

MBoC

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Protein-only (prion) epigenetic elements confer unique phenotypes by adopting alternate conformations that specify new traits. Given the conformational flexibility of prion proteins, protein-only inheritance requires efficient self-replication of the underlying conformation. To explore the cellular regulation of conformational self-replication and its phenotypic effects, we analyzed genetic interactions between [PSI ؉ ], a prion form of the S. cerevisiae Sup35 protein (Sup35 [PSI ؉ ] ), and the three N ␣ -acetyltransferases, NatA, NatB, and NatC, which collectively modify ϳ50% of yeast proteins. Although prion propagation proceeds normally in the absence of NatB or NatC, the [PSI ؉ ] phenotype is reversed in strains lacking NatA. Despite this change in phenotype, [PSI ؉ ] NatA mutants continue to propagate heritable Sup35 [PSI ؉ ] . This uncoupling of protein state and phenotype does not arise through a decrease in the number or activity of prion templates (propagons) or through an increase in soluble Sup35. Rather, NatA null strains are specifically impaired in establishing the translation termination defect that normally accompanies Sup35 incorporation into prion complexes. The NatA effect cannot be explained by the modification of known components of the [PSI ؉ ] prion cycle including Sup35; thus, novel acetylated cellular factors must act to establish and maintain the tight link between Sup35 [PSI ؉ ] complexes and their phenotypic effects. INTRODUCTIONThe transmission of phenotypes from one individual to another is a fundamental process in biology. Much of our understanding of these events arises from decades of study on nucleic acid metabolism, but new traits may also be passed between individuals without changes in nucleic acid content through a number of epigenetic mechanisms. One particularly intriguing example of such a process is the prion phenomenon, in which the activity of a protein is altered in a heritable way to transmit a new phenotype. How is such a feat accomplished? In 1967, Griffith proposed that some proteins, now known as prions (Prusiner, 1982), can adopt more than one stable form in vivo (Griffith, 1967). Since a protein's structure determines its function, two cells containing the same protein but in diffrent physical states will have distinct phenotypes. This protein-based process has been linked to a number of previously inexplicable events, including the development and spread of the transmissible spongiform encephalopathies in mammals (Prusiner, 1982) and the non-Mendelian inheritance of some traits in fungi (Wickner, 1994).Protein-based traits can only become transmissible, however, if the inherent structural flexibility of prion proteins can be constrained by regulatory mechanisms to create an epigenetic element. For example, if each newly synthesized prion polypeptide chain independently folded to a unique form, all cells would display the same phenotype, which would reflect the average of the accessible states. The appearance of distinct protein-based phenotypes suggests that ...

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Section: Sup35 Efficiently Joins Prion Complexes In Thementioning

confidence: 99%

Section: Imaging Digital Processing and Fluorescence Recovery Aftermentioning

confidence: 99%

mentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

Pezza

Langseth

Yamamoto

et al. 2009

MBoC

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Prions as Epigenetic Regulators of Phenotype in Fungi

Naeimi

Tuite

2012

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Structure and function of the molecular chaperone Hsp104 from yeast

Grimminger-Marquardt

Lashuel

2009

Biopolymers

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The molecular chaperone Hsp104 plays a central role in the clearance of aggregates after heat shock and the propagation of yeast prions. Hsp104's disaggregation activity and prion propagation have been linked to its ability to resolubilize or remodel protein aggregates. However, Hsp104 has also the capacity to catalyze protein aggregation of some substrates at specific conditions. Hence, it is a molecular chaperone with two opposing activities with respect to protein aggregation. In yeast models of Huntington's disease, Hsp104 is required for the aggregation and toxicity of polyglutamine (polyQ), but the expression of Hsp104 in cellular and animal models of Huntington's and Parkinson's disease protects against polyQ and α‐synuclein toxicity. Therefore, elucidating the molecular determinants and mechanisms underlying the ability of Hsp104 to switch between these two activities is of critical importance for understanding its function and could provide insight into novel strategies aimed at preventing or reversing the formation of toxic protein aggregation in systemic and neurodegenerative protein misfolding diseases. Here, we present an overview of the current molecular models and hypotheses that have been proposed to explain the role of Hsp104 in modulating protein aggregation and prion propagation. The experimental approaches and the evidences presented so far in relation to these models are examined. Our primary objective is to offer a critical review that will inspire the use of novel techniques and the design of new experiments to proceed towards a qualitative and quantitative understanding of the molecular mechanisms underlying the multifunctional properties of Hsp104 in vivo. © 2009 Wiley Periodicals, Inc. Biopolymers 93:252–276, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Hsp104-Dependent Remodeling of Prion Complexes Mediates Protein-Only Inheritance

Cited by 130 publications

References 63 publications

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

Prions as Epigenetic Regulators of Phenotype in Fungi

Structure and function of the molecular chaperone Hsp104 from yeast

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Hsp104-Dependent Remodeling of Prion Complexes Mediates Protein-Only Inheritance

Cited by 130 publications

References 63 publications

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI+] Phenotype

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI+] Phenotype

Prions as Epigenetic Regulators of Phenotype in Fungi

Structure and function of the molecular chaperone Hsp104 from yeast

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The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype