Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding

William M. Holmes, Brian K. Mannakee, Ryan N. Gutenkunst and Tricia R. Serio ()
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William M. Holmes: Cell Biology and Biochemistry, Brown University
Brian K. Mannakee: Graduate Interdisciplinary Program in Statistics, University of Arizona
Ryan N. Gutenkunst: University of Arizona
Tricia R. Serio: Cell Biology and Biochemistry, Brown University

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Amino-terminal acetylation is among the most ubiquitous of protein modifications in eukaryotes. Although loss of N-terminal acetylation is associated with many abnormalities, the molecular basis of these effects is known for only a few cases, where acetylation of single factors has been linked to binding avidity or metabolic stability. In contrast, the impact of N-terminal acetylation for the majority of the proteome, and its combinatorial contributions to phenotypes, are unknown. Here, by studying the yeast prion [PSI+], an amyloid of the Sup35 protein, we show that loss of N-terminal acetylation promotes general protein misfolding, a redeployment of chaperones to these substrates, and a corresponding stress response. These proteostasis changes, combined with the decreased stability of unacetylated Sup35 amyloid, reduce the size of prion aggregates and reverse their phenotypic consequences. Thus, loss of N-terminal acetylation, and its previously unanticipated role in protein biogenesis, globally resculpts the proteome to create a unique phenotype.

Date: 2014
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DOI: 10.1038/ncomms5383

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