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Molecular and Cellular Biology, September 2001, p. 6312-6321, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6312-6321.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of a Signal-Responsive Nuclear Export Sequence in Class II Histone Deacetylases

Timothy A. McKinsey, Chun Li Zhang, and Eric N. Olson*

Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148

Received 28 March 2001/Returned for modification 8 May 2001/Accepted 21 June 2001

Activation of muscle-specific genes by the MEF2 transcription factor is inhibited by class II histone deacetylases (HDACs) 4 and 5, which contain carboxy-terminal deacetylase domains and amino-terminal extensions required for association with MEF2. The inhibitory action of HDACs is overcome by myogenic signals which disrupt MEF2-HDAC interactions and stimulate nuclear export of these transcriptional repressors. Nucleocytoplasmic trafficking of HDAC5 is mediated by binding of the chaperone protein 14-3-3 to two phosphoserine residues (Ser-259 and Ser-498) in its amino-terminal extension. Here we show that HDAC4 and -5 each contain a signal-responsive nuclear export sequence (NES) at their extreme carboxy termini. The NES is conserved in another class II HDAC, HDAC7, but is absent in class I HDACs and the HDAC-related corepressor, MEF2-interacting transcription repressor. Our results suggest that this conserved NES is inactive in unphosphorylated HDAC5, which is localized to the nucleus, and that calcium-calmodulin-dependent protein kinase (CaMK)-dependent binding of 14-3-3 to phosphoserines 259 and 498 activates the NES, with consequent export of the transcriptional repressor to the cytoplasm. A single amino acid substitution in this NES is sufficient to retain HDAC5 in the nucleus in the face of CaMK signaling. These findings provide molecular insight into the mechanism by which extracellular cues alter chromatin structure to promote muscle differentiation and other MEF2-regulated processes.

* Corresponding author. Mailing address: Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390-9148. Phone: (214) 648-1187. Fax: (214) 648-1196. E-mail: eolson{at}hamon.swmed.edu.

Molecular and Cellular Biology, September 2001, p. 6312-6321, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6312-6321.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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