Prion-promoted phosphorylation of heterologous amyloid is coupled with ubiquitin-proteasome system inhibition and toxicity.
Mol Microbiol
; 93(5): 1043-56, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-25039275
ABSTRACT
Many neurodegenerative diseases are associated with conversion of a soluble protein into amyloid deposits, but how this is connected to toxicity remains largely unknown. Here, we explore mechanisms of amyloid associated toxicity using yeast. [PIN(+)], the prion form of the Q/N-rich Rnq1 protein, was known to enhance aggregation of heterologous proteins, including the overexpressed Q/N-rich amyloid forming domain of Pin4 (Pin4C), and Pin4C aggregates were known to attract chaperones, including Sis1. Here we show that in [PIN(+)] but not [pin(-)] cells, overexpression of Pin4C is deadly and linked to hyperphosphorylation of aggregated Pin4C. Furthermore, Pin4C aggregation, hyperphosphorylation and toxicity are simultaneously reversed by Sis1 overexpression. Toxicity may result from proteasome overload because hyperphosphorylated Pin4C aggregation is associated with reduced degradation of a ubiquitin-protein degradation reporter. Finally, hyperphosphorylation of endogenous full-length Pin4 was also facilitated by [PIN(+)], revealing that a prion can regulate post-translational modification of another protein.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
/
Fatores de Terminação de Peptídeos
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Proteínas de Saccharomyces cerevisiae
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Ubiquitina
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Complexo de Endopeptidases do Proteassoma
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Proteína Rad52 de Recombinação e Reparo de DNA
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Amiloide
Idioma:
En
Revista:
Mol Microbiol
Assunto da revista:
BIOLOGIA MOLECULAR
/
MICROBIOLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos