title: Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
abstract: Nucleophosmin (NPM) (B23) is an essential protein in mouse development and cell growth; however, it has been assigned numerous roles in very diverse cellular processes. Here, we present a unified mechanism for NPM's role in cell growth; NPM directs the nuclear export of both 40S and 60S ribosomal subunits. NPM interacts with rRNA and large and small ribosomal subunit proteins and also colocalizes with large and small ribosomal subunit proteins in the nucleolus, nucleus, and cytoplasm. The transduction of NPM shuttling-defective mutants or the loss of Npm1 inhibited the nuclear export of both the 40S and 60S ribosomal subunits, reduced the available pool of cytoplasmic polysomes, and diminished overall protein synthesis without affecting rRNA processing or ribosome assembly. While the inhibition of NPM shuttling can block cellular proliferation, the dramatic effects on ribosome export occur prior to cell cycle inhibition. Modest increases in NPM expression amplified the export of newly synthesized rRNAs, resulting in increased rates of protein synthesis and indicating that NPM is rate limiting in this pathway. These results support the idea that NPM-regulated ribosome export is a fundamental process in cell growth.
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Maggi
authors.forename: Michael
authors.initials: M
authors.lastname: Kuchenruether
authors.forename: David Y A
authors.initials: DY
authors.lastname: Dadey
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Schwope
authors.forename: Silvia
authors.initials: S
authors.lastname: Grisendi
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Jason D
authors.initials: JD
authors.lastname: Weber
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm; D006801:Humans; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000090243:Nucleophosmin; D011132:Polyribosomes; D014176:Protein Biosynthesis; D012335:RNA, Ribosomal / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D000090243:Nucleophosmin