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

Ziesché E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Müller H, Newel D, Kronich P, Schneider H, Dittrich-Breiholz O, Bhaskara S, Hiebert SW, Hottiger MO, Li H, Burstein E, Schmitz ML, Kracht M
Nucleic Acids Res. 2013 41 (1): 90-109

PMID: 23087373 · PMCID: PMC3592411 · DOI:10.1093/nar/gks916

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.

MeSH Terms (18)

Acetylation Animals Cell Line Chemokine CXCL2 Down-Regulation Histone Deacetylase Inhibitors Histone Deacetylases Humans Hydroxamic Acids Interleukin-1 Interleukin-8 Mice NF-kappa B Phosphorylation RNA Polymerase II Signal Transduction Transcription, Genetic Transcription Factor RelA

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