title: KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification.
abstract: Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification.
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.|Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors: Marjorie
authors: M
authors: Fournier
authors: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors: Meritxell
authors: M
authors: Orpinell
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Cédric
authors: C
authors: Grauffel
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Elisabeth
authors: E
authors: Scheer
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Jean-Marie
authors: JM
authors: Garnier
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Tao
authors: T
authors: Ye
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Virginie
authors: V
authors: Chavant
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Mathilde
authors: M
authors: Joint
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors: Fumiko
authors: F
authors: Esashi
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: Annick
authors: A
authors: Dejaegere
authors: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors: Pierre
authors: P
authors: Gönczy
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
authors: László
authors: L
authors: Tora
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002502:Centrioles / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry; D006801:Humans; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D006657:Histones; D008239:Lysine; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors; C501179:KAT2A protein, human; D000099224:p300-CBP-Associated Factor; C000620143:KAT2B protein, human; C490219:PLK4 protein, human