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Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3? via deacetylation of lysines within the 14-3-3? binding pocket.

ABSTRACT: The phospho-binding protein 14-3-3? acts as a signaling hub controlling a network of interacting partners and oncogenic pathways. We show here that lysines within the 14-3-3? 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 14-3-3?-phosphoprotein interactions. Through screening, we identified HDAC6 as the Lys(49)/Lys(120) deacetylase. Inhibition of HDAC6 blocks 14-3-3? 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 14-3-3? rescues both the HDAC6 inhibitor-induced loss of interaction and Ser(112)/Thr(642) phosphorylation. Furthermore, expression of the K49R/K120R mutant of 14-3-3? inhibits the cytotoxicity of HDAC6 inhibition. These data demonstrate a novel role for HDAC6 in controlling 14-3-3? binding activity.

SUBMITTER: Mortenson JB 

PROVIDER: S-EPMC4432270 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3ζ via deacetylation of lysines within the 14-3-3ζ binding pocket.

Mortenson Jeffrey B JB   Heppler Lisa N LN   Banks Courtney J CJ   Weerasekara Vajira K VK   Whited Matthew D MD   Piccolo Stephen R SR   Johnson William E WE   Thompson J Will JW   Andersen Joshua L JL  

The Journal of biological chemistry 20150313 20

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 inte  ...[more]

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