title: Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding.
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.
authors.affiliation: 1] Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, Rhode Island 02912, USA [2].
authors.forename: William M
authors.initials: WM
authors.lastname: Holmes
authors.affiliation: Graduate Interdisciplinary Program in Statistics, University of Arizona, 1548 East Drachman Street, Tucson, Arizona 85721, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Mannakee
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, 1007 East Lowell Street, Tucson, Arizona 85721, USA.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Gutenkunst
authors.affiliation: 1] Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, Rhode Island 02912, USA [2].
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Serio
mesh_terms: D000107:Acetylation; D011328:Prions / Q000378:metabolism*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011328:Prions; D029701:Saccharomyces cerevisiae Proteins