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Prion‐promoted phosphorylation of heterologous amyloid is coupled with ubiquitin‐proteasome system inhibition and toxicity
Author(s) -
Yang Zi,
Stone David E.,
Liebman Susan W.
Publication year - 2014
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12716
Subject(s) - hyperphosphorylation , proteasome , biology , ubiquitin , phosphorylation , toxicity , heterologous , microbiology and biotechnology , protein aggregation , amyloid (mycology) , biochemistry , chemistry , gene , botany , organic chemistry
Summary 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.