Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation

Maribel Parra, Herbert Kasler, Timothy A. McKinsey, Eric N. Olson, Eric Verdin

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

HDAC7, a class II histone deacetylase that is highly expressed in thymocytes, inhibits both transcription of the orphan steroid nuclear receptor Nur77 and induction of apoptosis in response to activation of the T-cell receptor (TCR). Here, we report that HDAC7 is exported to the cytoplasm by a calcium-independent signaling pathway after TCR activation. Protein kinase D1 (PKD1) was activated after TCR engagement, interacted with HDAC7, and phosphorylated three serines (Ser155, Ser318, and Ser 448) at its N terminus, leading to its export from the nucleus. Mutation of Ser155, Ser318, and Ser448 blocked the nucleocytoplasmic shuttling of HDAC7 in response to TCR activation, as did overexpression of a kinase-inactive form of PKD1. Consistent with the regulatory role of HDAC7 in Nur77 expression, PKD1 activation led to the transcriptional activation of Nur77 via myocyte enhancer factor 2-binding sites in its promoter. In a mouse model of negative selection, PKD1 was activated during thymocyte activation. These observations indicate that PKD1 regulates the expression of Nur77 during thymocyte activation at least in part by phosphorylating HDAC7.

Original languageEnglish (US)
Pages (from-to)13762-13770
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number14
DOIs
StatePublished - Apr 8 2005

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Cell Nucleus Active Transport
T-Cell Antigen Receptor
Protein Kinases
Chemical activation
Thymocytes
MEF2 Transcription Factors
Orphan Nuclear Receptors
Histone Deacetylases
Calcium Signaling
Steroid Receptors
Serine
Transcriptional Activation
Cytoplasm
Phosphotransferases
Transcription
Binding Sites
Cytoplasmic and Nuclear Receptors
Apoptosis
Mutation
Steroids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. / Parra, Maribel; Kasler, Herbert; McKinsey, Timothy A.; Olson, Eric N.; Verdin, Eric.

In: Journal of Biological Chemistry, Vol. 280, No. 14, 08.04.2005, p. 13762-13770.

Research output: Contribution to journalArticle

Parra, Maribel ; Kasler, Herbert ; McKinsey, Timothy A. ; Olson, Eric N. ; Verdin, Eric. / Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 14. pp. 13762-13770.
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