The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB

Elisabeth Ziesché, Daniela Kettner-Buhrow, Axel Weber, Tobias Wittwer, Liane Jurida, Johanna Soelch, Helmut Müller, Doris Newel, Petra Kronich, Heike Schneider, Oliver Dittrich-Breiholz, Srividya Bhaskara, Scott W. Hiebert, Michael O. Hottiger, Haiying Li, Ezra Burstein, M. Lienhard Schmitz, Michael Kracht

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-κB p65 and its deacetylation at various lysines. NF-κB p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-κB p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use.

Original languageEnglish (US)
Pages (from-to)90-109
Number of pages20
JournalNucleic acids research
Volume41
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Genetics

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