Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI+] prion in yeast and aggregation of Sup35in vitro

Derkatch, Irina L.; Uptain, Susan M.; Outeiro, Tiago F.; Krishnan, Rajaraman; Lindquist, Susan; Liebman, Susan W.

doi:10.1073/pnas.0404968101

Cited by 204 publications

(228 citation statements)

References 52 publications

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“…We have shown that the RAC alleviates the toxicity of expressing aggregation-prone proteins, suggesting that RAC function may reduce sequestration of essential factors by overexpressed proteins or, alternatively, indicative of a role for RAC in preventing nascent chains from adopting toxic, non-native conformations. Similarly, Rnq1, through its [PIN C ] factor activity, can template the folding of Sup35NM into relatively benign [PSI C ] amyloid conformations 21,22 and thus funnel excess Sup35NM away from adopting forms that could enhance sequestration of essential factors or potentially toxic misfolded forms. Consistent with this model, [PSI C ] cells are immune to the lethality of Sup35NM overexpression (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…21 which likely function as templates to cross-seed the de novo formation of [PSI C ]. 22 The Pin C phenotype commonly results from the [RNQ C ] prion. [23][24][25] Given the enhanced levels of prion formation in strains lacking RAC function, we asked whether the absence of the RAC bypasses the…”

Section: The Rac Antagonizes Induced and Spontaneous Formation Of Thementioning

confidence: 99%

“…21 Such aggregates, termed [PIN C ] factors (because they confer the Pin C phenotype, for [PSI C ] inducibility), are thought to serve as templates to inefficiently cross-seed de novo prion formation. 22 Although the Pin C phenotype commonly results from [RNQ C ], the prion form of the Rnq1 protein, [23][24][25] other proteins can also function as [PIN C ] factors and their levels can influence de novo prion formation. For example, Lsb2 is a [PIN C ] factor 23 that promotes [PSI C ] induction and whose levels are dramatically increased by thermal stress and decreased by proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

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The ribosome-associated complex antagonizes prion formation in yeast

Amor

Castanzo

Delany

et al. 2015

Prion

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ABSTRACT. The number of known fungal proteins capable of switching between alternative stable conformations is steadily increasing, suggesting that a prion-like mechanism may be broadly utilized as a means to propagate altered cellular states. To gain insight into the mechanisms by which cells regulate prion formation and toxicity we examined the role of the yeast ribosome-associated complex (RAC) in modulating both the formation of the [PSI C ] prion -an alternative conformer of Sup35 protein -and the toxicity of aggregation-prone polypeptides. The Hsp40 RAC chaperone Zuo1 anchors the RAC to ribosomes and stimulates the ATPase activity of the Hsp70 chaperone Ssb. We found that cells lacking Zuo1 are sensitive to over-expression of some aggregation-prone proteins, including the Sup35 prion domain, suggesting that co-translational protein misfolding increases in Dzuo1 strains. Consistent with this finding, Dzuo1 cells exhibit higher frequencies of spontaneous and induced prion formation. Cells expressing mutant forms of Zuo1 lacking either a C-terminal charged region required for ribosome association, or the J-domain responsible for Ssb ATPase stimulation, exhibit similarly high frequencies of prion formation. Our findings are consistent with a role for the RAC in chaperoning nascent Sup35 to regulate folding of the N-terminal prion domain as it emerges from the ribosome.

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Section: Discussionmentioning

confidence: 99%

Section: The Rac Antagonizes Induced and Spontaneous Formation Of Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The ribosome-associated complex antagonizes prion formation in yeast

Amor

Castanzo

Delany

et al. 2015

Prion

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“…Comparisons among the cellular and misfolded properties of the known Q/N-rich domain are shown in Table 1 [20][21][22][23][24][25][26][27][28][29][30][31] . The cellularfolded Q/N-rich domain shared key properties characteristic of the misfolded proteins, including insolubility and a tendency to form aggregates via intrinsic element-and self-interactions.…”

Section: Functional Substitutions Of Tdp-43 C Terminus By Prion Domainmentioning

confidence: 99%

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

et al. 2012

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“…In the case of the [PSI + ] prion, de novo appearance by overexpression of Sup35 depends on the presence of a pre-existing protein template, most frequently the [PIN + ] prion, encoded by Rnq1. 13,92,133 Recent studies in vitro and in vivo suggest that Rnq1 complexes are likely to effect Sup35 dynamics: Rnq1 complexes heterogeneously nucleate the formation of Sup35 complexes 135,136 and are required for conversion of these nascent Sup35 oligomers to a heritable form. 137 In addition to positive interactions between prions, co-existence of multiple prion forms, whether they are different sequences or different variants of the same sequence, is often disfavored.…”

Section: Modulating Prion Dynamicsmentioning

confidence: 99%