The Journal of Experimental Medicine
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Published online 28 February 2005 doi:10.1084/jem.20042034
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 793-804
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ARTICLE

 Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

Franck Dequiedt1, Johan Van Lint2, Emily Lecomte1, Viktor Van Duppen3, Thomas Seufferlein4, Jackie R. Vandenheede2, Ruddy Wattiez5, and Richard Kettmann1

1 Cellular and Molecular Biology Unit, Faculty of Agronomy, B-5030 Gembloux, Belgium
2 Division of Biochemistry, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
3 Division of Hematology, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
4 Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany
5 Laboratory of Biological Chemistry, Université de Mons-Hainaut, B-7000 Mons, Belgium

CORRESPONDENCE Franck Dequiedt: dequiedt.f{at}fsagx.ac.be

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection.

Abbreviations used: aa, amino acids; CaMK, Ca2+/calmodulin-dependent kinase; DP, double positive; GST, glutathione S-transferase; HDAC, histone deacetylase; IVK, in vitro kinase; PKC, protein kinase C; PKD, protein kinase D; SP, single positive.

F. Dequiedt and J. Van Lint contributed equally to this work.


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