A Promiscuous Prion: Efficient Induction of [URE3] Prion Formation by Heterologous Prion Domains

Ross, Carley D.; McCarty, Blake R.; Hamilton, Michael; Ben‐Hur, Asa; Ross, Eric D.

doi:10.1534/genetics.109.109322

Cited by 15 publications

(22 citation statements)

References 72 publications

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“…The effect on prion induction may be general as Lsb2 overexpression promoted the formation of another prion, [ RNQ + ], even when the Rnq1 protein was not overproduced. This agrees with previous observations that heterologous prion proteins may nucleate prion formation by each other (Ross et al, 2009). …”

Section: Discussionsupporting

confidence: 93%

Prion Induction by the Short-Lived, Stress-Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton

et al. 2011

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SUMMARY Yeast prions are self-perpetuating QN-rich amyloids, that control heritable traits and serve as a model for mammalian amyloidoses. De novo prion formation by overproduced prion protein is facilitated by other aggregated QN-rich protein(s), and is influenced by alterations of protein homeostasis. Here we explore the mechanism by which the Las17-binding protein Lsb2 (Pin3) promotes conversion of the translation termination factor Sup35 into its prion form [PSI+]. We show that Lsb2 localizes with some Sup35 aggregates and that Lsb2 is a short-lived protein whose levels are controlled via the ubiquitin-proteasome system and are dramatically increased by stress. Loss of Lsb2 decreases stability of [PSI+] after brief heat shock. Mutations interfering with Lsb2 ubiquitination increase prion induction, while a mutation eliminating association of Lsb2 with the actin cytoskeleton blocks its aggregation and prion–inducing ability. These findings directly implicate the UPS and actin cytoskeleton in regulating prions via a stress-inducible QN-rich protein.

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Section: Discussionsupporting

confidence: 93%

Prion Induction by the Short-Lived, Stress-Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton

et al. 2011

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“…Sequences were confirmed by DNA sequencing. Overexpression plasmids were generated by PCR amplification, restriction digest, and cloning into compatible sites in pKT24 (from Kim Taylor, NABI, Rockville, MD), which contains a GAL1 promoter, as previously described 35 .…”

Section: Methodsmentioning

confidence: 99%

“…Cultures were then normalized for OD 600, serially diluted, spotted onto synthetic solid media containing glucose or galactose lacking uracil, and grown at 30 °C for 2–3 days. HNRNPA2B1-Sup35 fusions were tested for prion formation and for stability and curability of the Ade+ phenotype as previously described 35 . Cytoductions were performed as previously described 38 .…”

Section: Methodsmentioning

confidence: 99%

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

Kim

Wang

et al. 2013

Nature

1,304

1,599

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SummaryAlgorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

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“…PCR products were digested with Bam HI and Pst I and inserted into Bam HI/ Pst I-cut pKT24 (from Kim Taylor, NABI, Rockville, MD), which contains the GAL1 promoter [54]. Ligation products were transformed into Escherichia coli and analyzed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

[PSI+] Maintenance Is Dependent on the Composition, Not Primary Sequence, of the Oligopeptide Repeat Domain

et al. 2011

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[PSI+], the prion form of the yeast Sup35 protein, results from the structural conversion of Sup35 from a soluble form into an infectious amyloid form. The infectivity of prions is thought to result from chaperone-dependent fiber cleavage that breaks large prion fibers into smaller, inheritable propagons. Like the mammalian prion protein PrP, Sup35 contains an oligopeptide repeat domain. Deletion analysis indicates that the oligopeptide repeat domain is critical for [PSI+] propagation, while a distinct region of the prion domain is responsible for prion nucleation. The PrP oligopeptide repeat domain can substitute for the Sup35 oligopeptide repeat domain in supporting [PSI+] propagation, suggesting a common role for repeats in supporting prion maintenance. However, randomizing the order of the amino acids in the Sup35 prion domain does not block prion formation or propagation, suggesting that amino acid composition is the primary determinant of Sup35's prion propensity. Thus, it is unclear what role the oligopeptide repeats play in [PSI+] propagation: the repeats could simply act as a non-specific spacer separating the prion nucleation domain from the rest of the protein; the repeats could contain specific compositional elements that promote prion propagation; or the repeats, while not essential for prion propagation, might explain some unique features of [PSI+]. Here, we test these three hypotheses and show that the ability of the Sup35 and PrP repeats to support [PSI+] propagation stems from their amino acid composition, not their primary sequences. Furthermore, we demonstrate that compositional requirements for the repeat domain are distinct from those of the nucleation domain, indicating that prion nucleation and propagation are driven by distinct compositional features.

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A Promiscuous Prion: Efficient Induction of [URE3] Prion Formation by Heterologous Prion Domains

Cited by 15 publications

References 72 publications

Prion Induction by the Short-Lived, Stress-Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton

Prion Induction by the Short-Lived, Stress-Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

[PSI+] Maintenance Is Dependent on the Composition, Not Primary Sequence, of the Oligopeptide Repeat Domain

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