Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3ζ via deacetylation of lysines within the 14-3-3ζ binding pocket.
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.
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Related Subject Headings
- bcl-Associated Death Protein
- Mutation, Missense
- Lysine
- Humans
- Histone Deacetylases
- Histone Deacetylase 6
- HEK293 Cells
- GTPase-Activating Proteins
- Cell Survival
- Biochemistry & Molecular Biology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- bcl-Associated Death Protein
- Mutation, Missense
- Lysine
- Humans
- Histone Deacetylases
- Histone Deacetylase 6
- HEK293 Cells
- GTPase-Activating Proteins
- Cell Survival
- Biochemistry & Molecular Biology