title: Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation.
abstract: Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran•GTP/Ran•GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed.
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: de Boor
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Knyphausen
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Kuhlmann
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wroblowski
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Brenig
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Scislowski
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Baldus
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany michael.lammers@uni-koeln.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lammers
mesh_terms: D000107:Acetylation; D000818:Animals; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D037761:Sirtuins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C062521:RCC1 protein, human; D006160:Guanosine Triphosphate; D037761:Sirtuins; D020931:ran GTP-Binding Protein; D008239:Lysine
keywords: Ran; genetic code expansion concept; lysine acetylation; nuclear cytosolic transport; nucleus