scholarly journals Elucidating the role of cofactors in mammalian prion propagation

Prion ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. 100-105 ◽  
Author(s):  
Surachai Supattapone
Keyword(s):  
Prion Propagation

Huntingtin Polyglutamine Fragments Are a Substrate for Hsp104 in Yeast

2021 ◽  
Author(s):  
Nicole J. Wayne ◽  
Katherine E. Dembny ◽  
Tyler Pease ◽  
Farrin Saba ◽  
Xiaohong Zhao ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Essential Role ◽  
Marked Effect ◽  
Yeast Prion ◽  
Rich Region ◽  
Polyglutamine Repeat ◽  
Prion Propagation

The aggregation of huntingtin fragments with expanded polyglutamine repeat regions (HttpolyQ) that cause Huntington’s disease depends on the presence of a prion with an amyloid conformation in yeast. As a result of this relationship, HttpolyQ aggregation indirectly depends on Hsp104 due to its essential role in prion propagation. We find that HttQ103 aggregation is directly affected by Hsp104 with and without the presence of [ RNQ + ] and [ PSI + ] prions. When we inactivate Hsp104 in the presence of prion, yeast have only one or a few large HttQ103 aggregates rather than numerous smaller aggregates. When we inactivate Hsp104 in the absence of prion, there is no significant aggregation of HttQ103; whereas with active Hsp104, HttQ103 aggregates slowly accumulate due to the severing of spontaneously nucleated aggregates by Hsp104. We do not observe either effect with HttQ103P, which has a polyproline-rich region downstream of the polyglutamine region, because HttQ103P does not spontaneously nucleate and Hsp104 does not efficiently sever the prion-nucleated HttQ103P aggregates. Therefore, the only role of Hsp104 in HttQ103P aggregation is to propagate yeast prion. In conclusion, because Hsp104 efficiently severs the HttQ103 aggregates, but not HttQ103P aggregates, it has a marked effect on the aggregation of HttQ103, but not HttQ103P.

scholarly journals Role of Hsp104 in the Propagation and Inheritance of the [Het-s] Prion

2007 ◽  
Vol 18 (12) ◽  
pp. 4803-4812 ◽  
Author(s):  
Laurent Malato ◽  
Suzana Dos Reis ◽  
Laura Benkemoun ◽  
Raimon Sabaté ◽  
Sven J. Saupe
Keyword(s):  
Meiotic Drive ◽  
Protein Aggregates ◽  
Propagation Rate ◽  
Podospora Anserina ◽  
Wild Type ◽  
Prion Propagation ◽  
Meiotic Instability

The chaperones of the ClpB/HSP100 family play a central role in thermotolerance in bacteria, plants, and fungi by ensuring solubilization of heat-induced protein aggregates. In addition in yeast, Hsp104 was found to be required for prion propagation. Herein, we analyze the role of Podospora anserina Hsp104 (PaHsp104) in the formation and propagation of the [Het-s] prion. We show that ΔPaHsp104 strains propagate [Het-s], making [Het-s] the first native fungal prion to be propagated in the absence of Hsp104. Nevertheless, we found that [Het-s]-propagon numbers, propagation rate, and spontaneous emergence are reduced in a ΔPaHsp104 background. In addition, inactivation of PaHsp104 leads to severe meiotic instability of [Het-s] and abolishes its meiotic drive activity. Finally, we show that ΔPaHSP104 strains are less susceptible than wild type to infection by exogenous recombinant HET-s(218–289) prion amyloids. Like [URE3] and [PIN+] in yeast but unlike [PSI+], [Het-s] is not cured by constitutive PaHsp104 overexpression. The observed effects of PaHsp104 inactivation are consistent with the described role of Hsp104 in prion aggregate shearing in yeast. However, Hsp104-dependency appears less stringent in P. anserina than in yeast; presumably because in Podospora prion propagation occurs in a syncitium.

scholarly journals Prion Propagation: The Role of Protein Dynamics

Prion ◽  
2007 ◽  
Vol 1 (1) ◽  
pp. 36-43 ◽  
Author(s):  
John A. Pezza ◽  
Tricia R. Serio
Keyword(s):  
Protein Dynamics ◽  
Prion Propagation

scholarly journals A Regulatory Role of the Rnq1 Nonprion Domain for Prion Propagation and Polyglutamine Aggregates

2008 ◽  
Vol 28 (10) ◽  
pp. 3313-3323 ◽  
Author(s):  
Hiroshi Kurahashi ◽  
Masao Ishiwata ◽  
Shoichiro Shibata ◽  
Yoshikazu Nakamura
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Sodium Dodecyl Sulfate ◽  
Crucial Role ◽  
De Novo ◽  
Self Regulation ◽  
Sodium Dodecyl ◽  
Protein Conformations ◽  
Chaperone Protein ◽  
Prion Propagation

ABSTRACT Prions are infectious, self-propagating protein conformations. Rnq1 is required for the yeast Saccharomyces cerevisiae prion [PIN +], which is necessary for the de novo induction of a second prion, [PSI +]. Here we isolated a [PSI +]-eliminating mutant, Rnq1Δ100, that deletes the nonprion domain of Rnq1. Rnq1Δ100 inhibits not only [PSI +] prion propagation but also [URE3] prion and huntingtin's polyglutamine aggregate propagation in a [PIN +] background but not in a [pin −] background. Rnq1Δ100, however, does not eliminate [PIN +]. These findings are interpreted as showing a possible involvement of the Rnq1 prion in the maintenance of heterologous prions and polyQ aggregates. Rnq1 and Rnq1Δ100 form a sodium dodecyl sulfate-stable and Sis1 (an Hsp40 chaperone protein)-containing coaggregate in [PIN +] cells. Importantly, Rnq1Δ100 is highly QN-rich and prone to self-aggregate or coaggregate with Rnq1 when coexpressed in [pin −] cells. However, the [pin −] Rnq1-Rnq1Δ100 coaggregate does not represent a prion-like aggregate. These findings suggest that [PIN +] Rnq1-Rnq1Δ100 aggregates interact with other transmissible and nontransmissible amyloids to destabilize them and that the nonprion domain of Rnq1 plays a crucial role in self-regulation of the highly reactive QN-rich prion domain of Rnq1.

scholarly journals The same but different: the role of Hsp70 in heat shock response and prion propagation

Prion ◽  
2018 ◽  
Vol 12 (3-4) ◽  
pp. 170-174 ◽  
Author(s):  
Linan Xu ◽  
Weibin Gong ◽  
Hong Zhang ◽  
Sarah Perrett ◽  
Gary W. Jones
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Shock Response ◽  
Prion Propagation

scholarly journals Role of the Cell Asymmetry Apparatus and Ribosome-Associated Chaperones in the Destabilization of a Saccharomyces cerevisiae Prion by Heat Shock

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 757-771 ◽  
Author(s):  
Rebecca L. Howie ◽  
Lina Manuela Jay-Garcia ◽  
Denis A. Kiktev ◽  
Quincy L. Faber ◽  
Margaret Murphy ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Heat Stress ◽  
Heat Shock ◽  
Translation Termination ◽  
Link Type ◽  
Gene Coding ◽  
Prion Propagation ◽  
Cell Asymmetry ◽  
And Control

Self-perpetuating transmissible protein aggregates, termed prions, are implicated in mammalian diseases and control phenotypically detectable traits in Saccharomyces cerevisiae. Yeast stress-inducible chaperone proteins, including Hsp104 and Hsp70-Ssa that counteract cytotoxic protein aggregation, also control prion propagation. Stress-damaged proteins that are not disaggregated by chaperones are cleared from daughter cells via mother-specific asymmetric segregation in cell divisions following heat shock. Short-term mild heat stress destabilizes [PSI+], a prion isoform of the yeast translation termination factor Sup35. This destabilization is linked to the induction of the Hsp104 chaperone. Here, we show that the region of Hsp104 known to be required for curing by artificially overproduced Hsp104 is also required for heat-shock-mediated [PSI+] destabilization. Moreover, deletion of the SIR2 gene, coding for a deacetylase crucial for asymmetric segregation of heat-damaged proteins, also counteracts heat-shock-mediated destabilization of [PSI+], and Sup35 aggregates are colocalized with aggregates of heat-damaged proteins marked by Hsp104-GFP. These results support the role of asymmetric segregation in prion destabilization. Finally, we show that depletion of the heat-shock noninducible ribosome-associated chaperone Hsp70-Ssb decreases heat-shock-mediated destabilization of [PSI+], while disruption of a cochaperone complex mediating the binding of Hsp70-Ssb to the ribosome increases prion loss. Our data indicate that Hsp70-Ssb relocates from the ribosome to the cytosol during heat stress. Cytosolic Hsp70-Ssb has been shown to antagonize the function of Hsp70-Ssa in prion propagation, which explains the Hsp70-Ssb effect on prion destabilization by heat shock. This result uncovers the stress-related role of a stress noninducible chaperone.

scholarly journals Evidence for a Protein Mutator in Yeast: Role of the Hsp70-Related Chaperone Ssb in Formation, Stability, and Toxicity of the [PSI] Prion

1999 ◽  
Vol 19 (12) ◽  
pp. 8103-8112 ◽  
Author(s):  
Yury O. Chernoff ◽  
Gary P. Newnam ◽  
Jaijit Kumar ◽  
Kim Allen ◽  
Amy D. Zink
Keyword(s):  
Guanidine Hydrochloride ◽  
Cellular Protein ◽  
Chemical Agent ◽  
Enzymatic System ◽  
Yeast Protein ◽  
Hsp70 Family ◽  
Polypeptide Folding ◽  
Prion Propagation ◽  
Extreme Sensitivity

ABSTRACT Propagation of the yeast protein-based non-Mendelian element [PSI], a prion-like form of the release factor Sup35, was shown to be regulated by the interplay between chaperone proteins Hsp104 and Hsp70. While overproduction of Hsp104 protein cures cells of [PSI], overproduction of the Ssa1 protein of the Hsp70 family protects [PSI] from the curing effect of Hsp104. Here we demonstrate that another protein of the Hsp70 family, Ssb, previously implicated in nascent polypeptide folding and protein turnover, exhibits effects on [PSI] which are opposite those of Ssa. Ssb overproduction increases, while Ssb depletion decreases, [PSI] curing by the overproduced Hsp104. Both spontaneous [PSI] formation and [PSI] induction by overproduction of the homologous or heterologous Sup35 protein are increased significantly in the strain lacking Ssb. This is the first example when inactivation of an unrelated cellular protein facilitates prion formation. Ssb is therefore playing a role in protein-based inheritance, which is analogous to the role played by the products of mutator genes in nucleic acid-based inheritance. Ssb depletion also decreases toxicity of the overproduced Sup35 and causes extreme sensitivity to the [PSI]-curing chemical agent guanidine hydrochloride. Our data demonstrate that various members of the yeast Hsp70 family have diverged from each other in regard to their roles in prion propagation and suggest that Ssb could serve as a proofreading component of the enzymatic system, which prevents formation of prion aggregates.

Sign in / Sign up

Export Citation Format

Share Document