title: Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3ζ via deacetylation of lysines within the 14-3-3ζ binding pocket.
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, Lys(49) and Lys(120), is critical for coordinating 14-3-3ζ-phosphoprotein interactions. Through screening, we identified HDAC6 as the Lys(49)/Lys(120) deacetylase. Inhibition of HDAC6 blocks 14-3-3ζ interactions with two well described interacting partners, Bad and AS160, which triggers their dephosphorylation at Ser(112) and Thr(642), respectively. Expression of an acetylation-refractory K49R/K120R mutant of 14-3-3ζ rescues both the HDAC6 inhibitor-induced loss of interaction and Ser(112)/Thr(642) 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.
authors.affiliation: From the Departments of Chemistry and Biochemistry and.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Mortenson
authors.affiliation: From the Departments of Chemistry and Biochemistry and.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Heppler
authors.affiliation: From the Departments of Chemistry and Biochemistry and.
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Banks
authors.affiliation: From the Departments of Chemistry and Biochemistry and.
authors.forename: Vajira K
authors.initials: VK
authors.lastname: Weerasekara
authors.affiliation: From the Departments of Chemistry and Biochemistry and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Whited
authors.affiliation: Biology, Brigham Young University, Provo, Utah 84602.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Piccolo
authors.affiliation: the Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts 02215, and.
authors.forename: William E
authors.initials: WE
authors.lastname: Johnson
authors.affiliation: the Institute for Genome Sciences and Policy, Duke University, Medical Center, Durham, North Carolina 27710.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: From the Departments of Chemistry and Biochemistry and jandersen@chem.byu.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Andersen
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D019943:Amino Acid Substitution; D001665:Binding Sites; D002470:Cell Survival / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; C494819:BAD protein, human; D020690:GTPase-Activating Proteins; C518767:TBC1D4 protein, human; C482983:YWHAE protein, human; D051025:bcl-Associated Death Protein; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008239:Lysine
keywords: 14-3- Protein; Apoptosis; Cell Signaling; Histone Deacetylase 6 (HDAC6); Metabolic Stress; Non-histone Acetylation; Stress