Yeast Prions: Proteins Templating Conformation and an Anti-prion System

Wickner, Reed B.; Edskes, Herman K.; Bateman, David A.; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E.; Mukhamedova, Maryam

doi:10.1371/journal.ppat.1004584

Cited by 8 publications

(6 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…So, it is inferred that, in a normal cell, cellular antiprion systems are continuously blocking prion generation, propagation, and toxicity (reviewed in refs. [20][21][22]. In the absence of an antiprion factor prions will appear with elevated frequency and many of those prion variants that arose in its absence are cured when the antiprion factor is restored to normal levels.…”

mentioning

confidence: 99%

Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants

Son

Wickner

2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor, Sup35p. For known pathogenic prions, such as [PSI+], a single protein can form an array of different amyloid structures (prion variants) each stably inherited and with differing biological properties. The ribosome-associated chaperones, Ssb1/2p (Hsp70s), and RAC (Zuo1p (Hsp40) and Ssz1p (Hsp70)), enhance de novo protein folding by protecting nascent polypeptide chains from misfolding and maintain translational fidelity by involvement in translation termination. Ssb1/2p and RAC chaperones were previously found to inhibit [PSI+] prion generation. We find that most [PSI+] variants arising in the absence of each chaperone were cured by restoring normal levels of that protein. [PSI+] variants hypersensitive to Ssb1/2p have distinguishable biological properties from those hypersensitive to Zuo1p or Ssz1p. The elevated [PSI+] generation frequency in each deletion strain is not due to an altered [PIN+], another prion that primes [PSI+] generation. [PSI+] prion generation/propagation may be inhibited by Ssb1/2/RAC chaperones by ensuring proper folding of nascent Sup35p, thus preventing its joining amyloid fibers. Alternatively, the effect of RAC/Ssb mutations on translation termination and the absence of an effect on the [URE3] prion suggest an effect on the mature Sup35p such that it does not readily join amyloid filaments. Ssz1p is degraded in zuo1Δ [psi-] cells, but not if the cells carry any of several [PSI+] variants. Our results imply that prions arise more frequently than had been thought but the cell has evolved exquisite antiprion systems that rapidly eliminate most variants.

show abstract

mentioning

confidence: 99%

Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants

Son

Wickner

2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…A given prion protein sequence can become any of many distinct prion variants/strains, with different biological properties as a result of different amyloid structures, each quite stably propagating (19,20). The yeast prion amyloids have a folded, parallel, in-register β-sheet architecture (21)(22)(23)(24), a structure that can explain how prion proteins can template their conformation, resulting in the stable propagation of different prion variants (25,26). These different prion variants act as alleles of a cytoplasmic protein-based gene.…”

mentioning

confidence: 99%

“…Most of the known antiprion systems are closely related to molecular chaperones, well-characterized protein quality-control systems for dealing with protein aggregates (reviewed in ref. 26). Deletion of ribosome-associated Hsp70 chaperones Ssb1p and Ssb2p leads to elevated frequency of [PSI+] formation, either spontaneously or induced by Sup35p overproduction (31).…”

mentioning

confidence: 99%

Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants

Son

Wickner

2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The yeast prion [PSI+] is a self-propagating amyloid of Sup35p with a folded in-register parallel β-sheet architecture. In a genetic screen for antiprion genes, using the yeast knockout collection, and, encoding nonsense-mediated mRNA decay (NMD) factors, were frequently detected. Almost all [PSI+] variants arising in the absence of Upf proteins were eliminated by restored normal levels of these proteins, and [PSI+] arises more frequently in mutants. Upf1p, complexed with Upf2p and Upf3p, is a multifunctional protein with helicase, ATP-binding, and RNA-binding activities promoting efficient translation termination and degradation of mRNAs with premature nonsense codons. We find that the curing ability of Upf proteins is uncorrelated with these previously reported functions but does depend on their interaction with Sup35p and formation of the Upf1p-Upf2p-Upf3p complex (i.e., the Upf complex). Indeed, Sup35p amyloid formation in vitro is inhibited by substoichiometric Upf1p. Inhibition of [PSI+] prion generation and propagation by Upf proteins may be due to the monomeric Upf proteins and the Upf complex competing with Sup35p amyloid fibers for available Sup35p monomers. Alternatively, the association of the Upf complex with amyloid filaments may block the addition of new monomers. Our results suggest that maintenance of normal protein-protein interactions prevents prion formation and can even reverse the process.

show abstract

“…Not all transmissible protein aggregates are cell-toxic, however. For example, yeast prions are transmissible [46] and fulfil physiological functions by increasing their adaptation to starvation [23,24,[47][48][49]. Similarly, DISC1 aggregates have been reported to lead to both loss of function due to the impairment of its binding to biological ligands (e.g.…”

Section: Discussionmentioning

confidence: 99%

Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine

et al. 2017

View full text Add to dashboard Cite

The disrupted-in-schizophrenia 1 (DISC1) gene was identified as a genetic risk factor for chronic mental illnesses (CMI) such as schizophrenia, bipolar disorder and severe recurrent depression. Insoluble aggregated DISC1 variants were found in the cingular cortex of sporadic, i.e. non-genetic, CMI patients. This suggests protein pathology as a novel, additional pathogenic mechanism, further corroborated in a recent transgenic rat model presenting DISC1 aggregates. Since the potential role of aggregation of DISC1 in sporadic CMI is unknown, we investigated whether DISC1 undergoes aggregation in cell culture and could spread between neuronal cells in a prion-like manner, as shown for amyloid proteins in neurodegenerative diseases. Co-culture experiments between donor cells forming DISC1 aggregates and acceptor cells showed that 4.5% of acceptor cells contained donor-derived DISC1 aggregates, thus indicating an efficient transfer in vitro. DISC1 aggregates were found inside tunnelling nanotubes (TNTs) and transfer was enhanced by increasing TNT formation and notably by dopamine treatment, which also induces DISC1 aggregation. These data indicate that DISC1 aggregates can propagate between cells similarly to prions, thus providing some molecular basis for the role of protein pathology in CMI.

show abstract

Yeast Prions: Proteins Templating Conformation and an Anti-prion System

Cited by 8 publications

References 29 publications

Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants

Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants

Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants

Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine

Contact Info

Product

Resources

About