Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion

Allen, Kim D.; Chernova, Tatiana A.; Tennant, Esther Paula; Wilkinson, Keith D.; Chernoff, Yury O.

doi:10.1074/jbc.m609597200

Cited by 74 publications

(102 citation statements)

References 58 publications

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“…Reducing ubiquitin (Ub) levels reduces the curing, while increasing Ub enhances it. 29,30 Sup35p is not ubiquitylated under either of these conditions, suggesting that Ub-mediated regulation or turnover of an unknown component is important for the curing process. The Hsp90 chaperone system, which serves as a post-translational regulator of many cellular processes, is also important for the curing mechanism.…”

Section: Hsp104mentioning

confidence: 94%

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Reidy

Masison

2011

Prion

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] provided a simple and satisfying explanation for a large body of puzzling data regarding these elements. It also established yeast as a system for studying amyloid and the prion-like behavior of proteins.The yeast system has since provided much insight into various aspects of prion biology. Having the advantages of facile and powerful genetics and molecular biology, the fungal prion field was first to confirm the prion hypothesis by demonstrating that proteins alone can act as infectious agents.2-6 Meeting the genetic criteria for yeast prions defined by Wickner, several other yeast proteins also have been found to be capable of behaving as infectious proteins. Like their mammalian counterparts, the basis of the prion phenotype is the propensity of these proteins to misfold and form highly ordered fibrous aggregates called amyloid.Since prions are improperly folded proteins, it is not surprising that alterations in abundance or function of protein chaperones and co-chaperones strongly influence yeast prion propagation. Many of these factors were identified on the basis of how their overexpression or depletion affects prion phenotypes. Molecular chaperones and co-chaperones overlap functionally, interact in complex ways, and their expression is feedback regulated. Therefore, it is difficult to know how altering abundance of any one of them influences cellular chaperone activity overall or whether any influence on prions can be attributed solely to the The yeast system has provided considerable insight into the biology of amyloid and prions. Here we focus on how alterations in abundance or function of protein chaperones and co-chaperones affect propagation of yeast prions. In spite of a considerable amount of information, a clear understanding of the molecular mechanisms underlying these effects remains wanting.

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Section: Hsp104mentioning

confidence: 94%

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Reidy

Masison

2011

Prion

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“…The 34-residue repeat ("tetratricopeptide")-containing cochaperones, Sti1p and Cpr7p, that mediate Hsp70-Hsp90 interactions have also been found to be involved in prion propagation ( Jones et al 2004;Reidy and Masison 2010), as have nucleotide exchange factors for Hsp70s, namely Sse1p and Fes1p (Fan et al 2007;. In addition to molecular chaperones, cytoskeletal proteins, elements of the ubiquitin system, and other factors modulate prion propagation in S. cerevisiae (Bailleul et al 1999;Bailleul-Winslett et al 2000;Allen et al 2007;Kryndushkin et al 2008).…”

Section: T He [Ure3] Prion Is a Self-propagating Amyloid (A Bmentioning

confidence: 99%

Molecular Chaperone Hsp104 Can Promote Yeast Prion Generation

et al. 2011

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ABSTRACT[URE3] is an amyloid-based prion of Ure2p, a regulator of nitrogen catabolism in Saccharomyces cerevisiae. The Ure2p of the human pathogen Candida albicans can also be a prion in S. cerevisiae. We find that overproduction of the disaggregating chaperone, Hsp104, increases the frequency of de novo [URE3] prion formation by the Ure2p of S. cerevisiae and that of C. albicans. This stimulation is strongly dependent on the presence of the [PIN 1 ] prion, known from previous work to enhance [URE3] prion generation. Our data suggest that transient Hsp104 overproduction enhances prion generation through persistent effects on Rnq1 amyloid, as well as during overproduction by disassembly of amorphous Ure2 aggregates (generated during Ure2p overproduction), driving the aggregation toward the amyloid pathway. Overproduction of other major cytosolic chaperones of the Hsp70 and Hsp40 families (Ssa1p, Sse1p, and Ydj1p) inhibit prion formation, whereas another yeast Hsp40, Sis1p, modulates the effects of Hsp104p on both prion induction and prion curing in a prion-specific manner. The same factor may both enhance de novo prion generation and destabilize existing prion variants, suggesting that prion variants may be selected by changes in the chaperone network.

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“…Third, the steady-state size of SDS-resistant Sup35 aggregates increases in [PSI ϩ ] strains deficient in Hsp104, Hsp70, or Hsp70 cochaperones (Eaglestone et al, 2000;Wegrzyn et al, 2001;Cox et al, 2003;Kryndushkin et al, 2003;Jones et al, 2004;Song et al, 2005;Fan et al, 2007;Kryndushkin and Wickner, 2007;SatputeKrishnan et al, 2007;Sadlish et al, 2008), an observation that is completely opposed to our findings for NatA mutants ( Figure 5C). In addition to these factors, the ubiquitin-conjugating enzyme Ubc4 and the Hsp70 family members Ssb1 and Ssb2 are predicted or proven substrates for NatA (Huang et al, 1987;Polevoda et al, 1999), are modifiers of the [PSI ϩ ] prion cycle Allen et al, 2007), and have demonstrated synthetic interactions with NatA (Gautschi et al, 2003;Pan et al, 2006). Despite these intriguing connections, ⌬ubc4 and ⌬ssb1⌬ssb2 strains, unlike NatA null strains, display the [PSI ϩ ] nonsense suppression phenotype, indicating that they are unlikely to be the crucial NatA targets.…”

Section: Discussionmentioning

confidence: 99%

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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Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion

Cited by 74 publications

References 58 publications

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Molecular Chaperone Hsp104 Can Promote Yeast Prion Generation

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

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Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion

Cited by 74 publications

References 58 publications

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Modulation and elimination of yeast prions by protein chaperones and co-chaperones.

Molecular Chaperone Hsp104 Can Promote Yeast Prion Generation

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

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