A brief overview of the Swi1 prion—[SWI+]

Goncharoff, Dustin K.; Du, Zhiqiang; Li, Liming

doi:10.1093/femsyr/foy061

Cited by 18 publications

(13 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One would expect that the translation of the stretches of identical amino acids found in these specific proteins [52] is particularly sensitive to reduced translation speed. Indeed, synthesis of the Gln-rich prion Rnq1 is severely impaired by the absence of mcm 5 s 2 U34 and this defect can be rescued by overexpression of tRNA Gln UUG [29], but it is not known if the absence of t 6 A affects the synthesis of the Asn/Thr rich prion SWI1 [53].…”

Section: Introductionmentioning

confidence: 99%

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

et al. 2020

View full text Add to dashboard Cite

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t6A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm5s2U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequence is a subsequent increase in protein aggregates and aberrant morphology. Proteomic analysis of the t6A-deficient strain (sua5 mutant) revealed a global mistranslation leading to protein aggregation without regard to physicochemical properties or t6A-dependent or biased codon usage in parent genes. However, loss of sua5 led to increased expression of soluble proteins for mitochondrial function, protein quality processing/trafficking, oxidative stress response, and energy homeostasis. These results point to a global function for t6A in protein homeostasis very similar to mcm5/s2U modifications.

show abstract

Section: Introductionmentioning

confidence: 99%

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

et al. 2020

View full text Add to dashboard Cite

show abstract

“…FLO1 , FLO5 , FLO9 and FLO10 ) as well as the epigenetically controlled gene FLO11 . Likewise, a yeast chromatin remodeling complex protein, SWI1, is required for the expression of telomerically located and epigenetically controlled FLO genes [63]. Interestingly, SWI1 can form infectious prion aggregates [12] reminiscent of the amyloid CREST aggregates seen here.…”

Section: Discussionmentioning

confidence: 99%

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Park

Watanabe

et al. 2019

PLoS Genet

View full text Add to dashboard Cite

Proteins associated with familial neurodegenerative disease often aggregate in patients’ neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1 , reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1 , encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of amyloid-like protein. Like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [ PIN + ] prion and reduced by deletion of the HSP104 chaperone required for the propagation of many yeast prions. Likewise, deletion of PBP1 reduced CREST toxicity and aggregation. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Downregulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to largely rescue the severe degenerative phenotype induced by human CREST. Overexpression caused considerable co-localization of CREST and PBP1/ATXN2 in cytoplasmic foci in both yeast and mammalian cells. Thus, co-aggregation of CREST and PBP1/ATXN2 may serve as one of the mechanisms of PBP1/ATXN2-mediated toxicity. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by PBP1/ATXN2 , suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

show abstract

“…FLO1, FLO5, FLO9 and FLO10) as well as the epigenetically controlled gene FLO11. Likewise, a yeast chromatin remodeling complex protein, SWI1, is required for the expression of telomerically located and epigenetically controlled FLO genes [88]. Interestingly, SWI1…”

Section: Discussionmentioning

confidence: 99%

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Park

Watanabe

et al. 2018

Preprint

View full text Add to dashboard Cite

Proteins associated with familial neurodegenerative disease often aggregate in patients' neurons.Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets.Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and, like the yeast chromatinremodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN + ] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Down regulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to almost entirely rescue the severe degenerative phenotype induced by human CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases. Author summaryMutations in the calcium-responsive transactivator (CREST) protein have been shown to cause amyotrophic lateral sclerosis (ALS). Here we show that the human CREST protein expressed in yeast forms nuclear aggregates and is toxic. We also show that ATXN2, previously shown to modify ALS toxicity caused by mutations in the TDP-43 encoding gene, also modifies toxicity of CREST expressed in either yeast or flies. These results extend the spectrum of ALS associated proteins affected by ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

show abstract

A brief overview of the Swi1 prion—[SWI+]

Cited by 18 publications

References 86 publications

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Contact Info

Product

Resources

About