title: Prion-promoted phosphorylation of heterologous amyloid is coupled with ubiquitin-proteasome system inhibition and toxicity.
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.
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yang
authors.forename: David E
authors.initials: DE
authors.lastname: Stone
authors.forename: Susan W
authors.initials: SW
authors.lastname: Liebman
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D011328:Prions; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000682:Amyloid; C523554:PIN4 protein, S cerevisiae; D010454:Peptide Termination Factors; D011328:Prions; C404807:RNQ1 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex