Keywords

14-3- Protein, Apoptosis, Cell Signaling, Histone Deacetylase 6 (HDAC6), Stress, Metabolic Stress, Non-histone Acetylation

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.

Original Publication Citation

Mortenson JB, Heppler LN, Banks CJ, Weerasekara VK, Whited MD, Piccolo SR, Johnson WE, Thompson JW, Andersen JL. “Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3 via deacetylation of lysines within the 14-3-3 binding pocket”. Journal of Biological Chemistry, 2015 May 15;290(20):12487-96

Document Type

Peer-Reviewed Article

Publication Date

2015-05-15

Publisher

American Society for Biochemistry and Molecular Biology

Language

English

College

Life Sciences

Department

Biology

University Standing at Time of Publication

Associate Professor

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