title: The nascent polypeptide-associated complex is a key regulator of proteostasis.
abstract: The adaptation of protein synthesis to environmental and physiological challenges is essential for cell viability. Here, we show that translation is tightly linked to the protein-folding environment of the cell through the functional properties of the ribosome bound chaperone NAC (nascent polypeptide-associated complex). Under non-stress conditions, NAC associates with ribosomes to promote translation and protein folding. When proteostasis is imbalanced, NAC relocalizes from a ribosome-associated state to protein aggregates in its role as a chaperone. This results in a functional depletion of NAC from the ribosome that diminishes translational capacity and the flux of nascent proteins. Depletion of NAC from polysomes and re-localisation to protein aggregates is observed during ageing, in response to heat shock and upon expression of the highly aggregation-prone polyglutamine-expansion proteins and Aβ-peptide. These results demonstrate that NAC has a central role as a proteostasis sensor to provide the cell with a regulatory feedback mechanism in which translational activity is also controlled by the folding state of the cellular proteome and the cellular response to stress.
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirstein-Miles
authors.forename: Annika
authors.initials: A
authors.lastname: Scior
authors.forename: Elke
authors.initials: E
authors.lastname: Deuerling
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018832:Molecular Chaperones; D010455:Peptides; C096099:nascent-polypeptide-associated complex; C097188:polyglutamine