14-3-3 Regulates The Nuclear Import Of Class Iia Histone Deacetylases

Proteins that influence gene expression are called histone deacetylases (HDACs). These enzymes are responsible for a range of cellular functions. For example, they influence epigenetic changes and can assemble into multiprotein complexes. The enzymatic activities of these proteins are regulated at multiple levels and are subject to a variety of physiological responses.

The nuclear import of HDAC4 is regulated by the 14-3-3 protein. This protein shuttles between the cytoplasm and the nucleus. The phosphorylation-induced 14-3-3 binding biases the nuclear import of HDAC4 to the cytoplasm.

It is also important to note that CaM inhibits CaMKII activity. CaM levels decline during normal culture. Inhibition of CaM by KN93 prevented this shift in HDAC4 nuclear import. However, this inhibition did not result in a significant increase in nuclear export of HDAC4.

CKIP-1 is a protein that interacts with HDAC4 and PP2AC. When deficient in this protein, it promotes the nuclear export of HDAC4 and increases the activity of MEF2C. The mutant protein also upregulates the expression of HDAC4 target genes.

In failing human hearts, chronic CaMKII phosphorylation inhibits the nuclear import of HDAC4. Thus, inhibition of PKA inhibits b-AR, which limits HDAC4 nuclear export and MEF2 expression.

Mutations in HDAC5 and the 14-3-3 proteins have a profound effect on the underlying mechanisms of their interaction. Mutations of S259/498A in HDAC5 increase association with the corepressor complex, while S278/279A decreases corepressor complex association and increases 14-3-3 proteins in VSMCs.

In a study in adult ventricular myocytes, Ang II activates CaMKII and inhibits the nuclear import of HDAC4 and HDAC5. Inhibition of the activity of HDAC4 and HDAC5 by KN93 prevented the Ang II-induced nuclear depletion of HDAC4 and HDAC5 in these cells.