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Mol. Cell. Biol. doi:10.1128/MCB.01611-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Histone Deacetylase 4 Confers CaM Kinase II Responsiveness to Histone Deacetylase 5 by Oligomerization

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cardiology, University of Heidelberg, Heidelberg Germany; Gilead Colorado, Inc., 7575 West 103rd Ave., Westminster, Colorado 80021, USA

	Abstract

Calcium, calmodulin-dependent protein kinase II (CaMKII) phosphorylates histone deacetylase 4 (HDAC4), a class IIa HDAC, resulting in cytosolic accumulation of HDAC4 and de-repression of the MEF2 transcription factor. Phosphorylation by CaMKII requires docking of the kinase to a specific domain of HDAC4 not present in other HDACs. Paradoxically, however, CaMKII signaling can also promote the nuclear export of other class IIa HDACs, such as HDAC5. Here, we show that HDAC4 and HDAC5 form homo- and hetero-oligomers via a conserved coiled-coil domain near their amino-termini. Whereas HDAC5 alone is unresponsive to CaMKII, it becomes responsive to CaMKII in the presence of HDAC4. The acquisition of CaMKII responsiveness by HDAC5 is mediated by its direct association with HDAC4 and can occur by phosphorylation of HDAC4 or by trans-phosphorylation by CaMKII bound to HDAC4. Thus, HDAC4 integrates upstream Ca²⁺-dependent signals via its association with CaMKII and transmits these signals to HDAC5 by protein-protein interactions. We conclude that HDAC4 represents a point of convergence of CaMKII signaling to downstream HDAC-regulated genes and suggest that modulation of the interaction of CaMKII and HDAC4 represents a means of regulating CaMKII-dependent gene programs.

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