Disrupting the cortical actin cytoskeleton points to two distinct mechanisms of yeast [PSI+] prion formation.

PLoS Genet

University of Manchester, Faculty of Biology, Medicine and Health, The Michael Smith Building, Manchester, Unted Kindom.

Published: April 2017

Mammalian and fungal prions arise de novo; however, the mechanism is poorly understood in molecular terms. One strong possibility is that oxidative damage to the non-prion form of a protein may be an important trigger influencing the formation of its heritable prion conformation. We have examined the oxidative stress-induced formation of the yeast [PSI+] prion, which is the altered conformation of the Sup35 translation termination factor. We used tandem affinity purification (TAP) and mass spectrometry to identify the proteins which associate with Sup35 in a tsa1 tsa2 antioxidant mutant to address the mechanism by which Sup35 forms the [PSI+] prion during oxidative stress conditions. This analysis identified several components of the cortical actin cytoskeleton including the Abp1 actin nucleation promoting factor, and we show that deletion of the ABP1 gene abrogates oxidant-induced [PSI+] prion formation. The frequency of spontaneous [PSI+] prion formation can be increased by overexpression of Sup35 since the excess Sup35 increases the probability of forming prion seeds. In contrast to oxidant-induced [PSI+] prion formation, overexpression-induced [PSI+] prion formation was only modestly affected in an abp1 mutant. Furthermore, treating yeast cells with latrunculin A to disrupt the formation of actin cables and patches abrogated oxidant-induced, but not overexpression-induced [PSI+] prion formation, suggesting a mechanistic difference in prion formation. [PIN+], the prion form of Rnq1, localizes to the IPOD (insoluble protein deposit) and is thought to influence the aggregation of other proteins. We show Sup35 becomes oxidized and aggregates during oxidative stress conditions, but does not co-localize with Rnq1 in an abp1 mutant which may account for the reduced frequency of [PSI+] prion formation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393896PMC
http://dx.doi.org/10.1371/journal.pgen.1006708DOI Listing

Publication Analysis

Top Keywords

[psi+] prion
36
prion formation
32
prion
13
formation
11
[psi+]
9
cortical actin
8
actin cytoskeleton
8
yeast [psi+]
8
oxidative stress
8
stress conditions
8

Similar Publications

The dynamic balance between formation and disaggregation of amyloid fibrils is associated with many neurodegenerative diseases. Multiple chaperones interact with and disaggregate amyloid fibrils, which impacts amyloid propagation and cellular phenotypes. However, it remains poorly understood whether and how site-specific binding of chaperones to amyloids facilitates the concerted disaggregation process and modulates physiological consequences in vivo.

View Article and Find Full Text PDF

[PSI]-CIC: A Deep-Learning Pipeline for the Annotation of Sectored Saccharomyces cerevisiae Colonies.

Bull Math Biol

December 2024

Department of Applied Mathematics, University of California, Merced, 5200 N Lake Drive, Merced, CA, 95343, USA.

The prion phenotype in yeast manifests as a white, pink, or red color pigment. Experimental manipulations destabilize prion phenotypes, and allow colonies to exhibit (red) sectored phenotypes within otherwise completely white colonies. Further investigation of the size and frequency of sectors that emerge as a result of experimental manipulation is capable of providing critical information on mechanisms of prion curing, but we lack a way to reliably extract this information.

View Article and Find Full Text PDF

Compositionally biased regions (CBRs), ie, tracts that are dominated by a subset of residue types, are common features of eukaryotic proteins. These are often found bounded within or almost coterminous with intrinsically disordered or 'natively unfolded' parts. Here, it is investigated how the function of such intrinsically disordered compositionally biased regions (ID-CBRs) is directly linked to their compositional traits, focusing on the well-characterized yeast () proteome as a test case.

View Article and Find Full Text PDF

Prion variants are self-perpetuating conformers of a single protein that assemble into amyloid fibers and confer unique phenotypic states. Multiple prion variants can arise, particularly in response to changing environments, and interact within an organism. These interactions are often competitive, with one variant establishing phenotypic dominance over the others.

View Article and Find Full Text PDF

Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation.

PLoS Genet

February 2024

Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom.

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!