KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

Marjorie Fournier, Meritxell Orpinell, Cédric Grauffel, Elisabeth Scheer, Jean-Marie Garnier, Tao Ye, Virginie Chavant, Mathilde Joint, Fumiko Esashi, Annick Dejaegere, Pierre Gönczy () and László Tora ()
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Marjorie Fournier: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Meritxell Orpinell: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL)
Cédric Grauffel: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Elisabeth Scheer: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Jean-Marie Garnier: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Tao Ye: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Virginie Chavant: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Mathilde Joint: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Fumiko Esashi: Sir William Dunn School of Pathology, University of Oxford
Annick Dejaegere: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Pierre Gönczy: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL)
László Tora: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13227

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