Regulation of histone deacetylase 4 by binding of 14-3-3 proteins

Histone (de)acetylation is important for the regulation of Fundamental biol ogical processes such as gene expression and DNA recombination. Distinct cl asses of histone deacetylases (HDACs) have been identified, but how they ar e regulated in vivo remains largely unexplored. Here we describe results de monstrating that HDAC4, a member of class II human HDACs, is localized in t he cytoplasm and/or the nucleus. Moreover, we have found that HDAC4 interac ts with the 14-3-3 family of proteins that are known to bind specifically t o conserved phosphoserine-containing motifs. Deletion analyses suggested th at S246, S467, and S632 of HDAC4 mediate this interaction. Consistent with this, alanine substitutions of these serine residues abrogated 14-3-3 bindi ng. Although these substitutions had minimal effects on the deacetylase act ivity of HDAC4 they stimulated its nuclear localization and thus led to enh anced transcriptional repression. These results indicate that 14-3-3 protei ns negatively regulate HDAC4 by preventing its nuclear localization and the reby uncover a novel regulatory mechanism for HDACs.