title: Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα by Lysine Acetylation.
abstract: Rho proteins are small GTP/GDP-binding proteins primarily involved in cytoskeleton regulation. Their GTP/GDP cycle is often tightly connected to a membrane/cytosol cycle regulated by the Rho guanine nucleotide dissociation inhibitor α (RhoGDIα). RhoGDIα has been regarded as a housekeeping regulator essential to control homeostasis of Rho proteins. Recent proteomic screens showed that RhoGDIα is extensively lysine-acetylated. Here, we present the first comprehensive structural and mechanistic study to show how RhoGDIα function is regulated by lysine acetylation. We discover that lysine acetylation impairs Rho protein binding and increases guanine nucleotide exchange factor-catalyzed nucleotide exchange on RhoA, these two functions being prerequisites to constitute a bona fide GDI displacement factor. RhoGDIα acetylation interferes with Rho signaling, resulting in alteration of cellular filamentous actin. Finally, we discover that RhoGDIα is endogenously acetylated in mammalian cells, and we identify CBP, p300, and pCAF as RhoGDIα-acetyltransferases and Sirt2 and HDAC6 as specific deacetylases, showing the biological significance of this post-translational modification.
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Kuhlmann
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wroblowski
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Knyphausen
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: de Boor
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Brenig
authors.affiliation: the Institute for Genetics, Zülpicher Strasse 47a, University of Cologne, 50674 Cologne, Germany.
authors.forename: Anke Y
authors.initials: AY
authors.lastname: Zienert
authors.affiliation: the Institute for Genetics, Zülpicher Strasse 47a, University of Cologne, 50674 Cologne, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Meyer-Teschendorf
authors.affiliation: the Institute for Genetics, Zülpicher Strasse 47a, University of Cologne, 50674 Cologne, Germany,; the Paul-Ehrlich-Institute, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany, and.
authors.forename: Gerrit J K
authors.initials: GJK
authors.lastname: Praefcke
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: the Institute for Biochemistry, Zülpicher Strasse 47, University of Cologne, 50674 Cologne, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Schacherl
authors.affiliation: the Institute for Biochemistry, Zülpicher Strasse 47, University of Cologne, 50674 Cologne, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.affiliation: the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
authors.affiliation: the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chin
authors.affiliation: From the Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, University of Cologne, 50931 Cologne, Germany,. Electronic address: michael.lammers@uni-koeln.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lammers
mesh_terms: D000107:Acetylation; D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D006150:Guanine Nucleotides / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D056565:Sirtuin 2 / Q000378:metabolism; D058207:Sumoylation; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000032:analysis / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006150:Guanine Nucleotides; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020742:rhoA GTP-Binding Protein; D008239:Lysine
keywords: Ras homolog gene family, member A (RhoA); Rho (Rho GTPase); acetylation; acetyltransferase; guanine-nucleotide-dissociation inhibitor alpha; histone deacetylase (HDAC); lysine acetylation; lysine acetyltransferase; post-translational modification (PTM); sirtuin