Histone Deacetylase 6 (HDAC6) Promotes the Pro-survival Activity of 14-3-3ζ via Deacetylation of Lysines within the 14-3-3ζ Binding Pocket |
| |
| Authors: | Jeffrey B Mortenson Lisa N Heppler Courtney J Banks Vajira K Weerasekara Matthew D Whited Stephen R Piccolo William E Johnson J Will Thompson Joshua L Andersen |
| |
| Institution: | From the Departments of ‡Chemistry and Biochemistry and ;§Biology, Brigham Young University, Provo, Utah 84602, ;the ¶Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts 02215, and ;the ‖Institute for Genome Sciences and Policy, Duke University, Medical Center, Durham, North Carolina 27710 |
| |
| Abstract: | The phospho-binding protein 14-3-3ζ acts as a signaling hub controlling a network of interacting partners and oncogenic pathways. We show here that lysines within the 14-3-3ζ binding pocket and protein-protein interface can be modified by acetylation. The positive charge on two of these lysines, Lys49 and Lys120, is critical for coordinating 14-3-3ζ-phosphoprotein interactions. Through screening, we identified HDAC6 as the Lys49/Lys120 deacetylase. Inhibition of HDAC6 blocks 14-3-3ζ interactions with two well described interacting partners, Bad and AS160, which triggers their dephosphorylation at Ser112 and Thr642, respectively. Expression of an acetylation-refractory K49R/K120R mutant of 14-3-3ζ rescues both the HDAC6 inhibitor-induced loss of interaction and Ser112/Thr642 phosphorylation. Furthermore, expression of the K49R/K120R mutant of 14-3-3ζ inhibits the cytotoxicity of HDAC6 inhibition. These data demonstrate a novel role for HDAC6 in controlling 14-3-3ζ binding activity. |
| |
| Keywords: | 14-3- Protein Apoptosis Cell Signaling Histone Deacetylase 6 (HDAC6) Stress Metabolic Stress Non-histone Acetylation |
|
|
