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, Brigham Young University
Lisa N. Heppler, Brigham Young University
Courtney J. Banks, Brigham Young University
Vajira K. Weerasekara, Brigham Young University
Matthew D. Whited, Brigham Young University
Stephen R. Piccolo, Brigham Young University
William E. Johnson, Boston University School of Medicine
J. Will Thompson, Duke University
Joshua L. Andersen, Brigham Young University

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

BYU ScholarsArchive Citation

Mortenson, Jeffrey B.; Heppler, Lisa N.; Banks, Courtney J.; Weerasekara, Vajira K.; Whited, Matthew D.; Piccolo, Stephen R.; Johnson, William E.; Thompson, J. Will; and Andersen, Joshua L., "Histone Deacetylase 6 (HDAC6) Promotes the Pro-survival Activity of 14-3-3ζ via Deacetylation of Lysines within the 14-3-3ζ Binding Pocket" (2015). Faculty Publications. 7465.
https://scholarsarchive.byu.edu/facpub/7465

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

Copyright Use Information

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