Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates

Abstract

Acetylation of lysines is a prominent form of modification in mammalian proteins. Deacetylation of proteins is catalyzed by histone deacetylases, traditionally named after their role in histone deacetylation, transcriptional modulation, and epigenetic regulation. Despite the link between histone deacetylases and chromatin structure, some of the histone deacetylases reside in various compartments in the cytoplasm. Here, we review how these cytoplasmic histone deacetylases are regulated, the identification of nonhistone substrates, and the functional implications of their nondeacetylase enzymatic activities.

Figure 1

A model on the regulation of nucleo-cytoplasmic shuttling and the functions of HDAC4. HDAC4 dynamically shuttles between nucleus and cytoplasm, depending on its phosphorylation status. Phosphorylated HDAC4 binds to 14-3-3 and remains in the cytoplasm. The cytoplasmic form of HDAC4 might possess protein deacetylase activity. Whether cytoplasmic HDAC4 possesses SUMO E3 ligase activity remains unclear. Dephosphorylated HDAC4 is imported into the nucleus, where reduction of HDAC4 by Trx1 favors nuclear retention. Oxidases that catalyze the reverse reaction remain to be identified. Nuclear HDAC4 possesses deacetylase as well as SUMO E3 ligase activities on substrates indicated in the figure.

Figure 2

Regulation and functional ramifications of the HDAC6 deacetylase activity. Interaction with protein partners reduces protein deacetylase activity of HDAC6, which is important for the deacetylation of substrate proteins and cellular effects as indicated.

Figure 3

A model of how HDAC6/Hsp90 and HDAC10/Hsp70 collaboratively work as protein chaperones. Deacetylation of Hsp90 catalyzed by HDAC6 might prime its chaperone function. Deacetylated Hsp70, catalyzed by HDAC10 or by another deacetylase, joins the Hsp90/chaperone client complexes to help with correct folding of the clients. Acetylation of Hsp70, a likely result of HDAC10 deregulation, might cause incorrect folding of proteins or facilitate the subsequent degradation of misfolded proteins.