TY - JOUR
T1 - The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB
AU - Ziesché, Elisabeth
AU - Kettner-Buhrow, Daniela
AU - Weber, Axel
AU - Wittwer, Tobias
AU - Jurida, Liane
AU - Soelch, Johanna
AU - Müller, Helmut
AU - Newel, Doris
AU - Kronich, Petra
AU - Schneider, Heike
AU - Dittrich-Breiholz, Oliver
AU - Bhaskara, Srividya
AU - Hiebert, Scott W.
AU - Hottiger, Michael O.
AU - Li, Haiying
AU - Burstein, Ezra
AU - Schmitz, M. Lienhard
AU - Kracht, Michael
N1 - Funding Information:
Deutsche Forschungsgemeinschaft (DFG) [Kr1143/5-3 and Kr1143/7-1] and [SFB566/Z02 and TRR81/B2]; [SCHM 1417/4-2, SCHM 1417/7-1, SCHM 1417/8-1, GRK 1566/1 to M.L.S.]; Deutscher akademischer Austauschdienst [A/08/98404 to M.L.S]; Work from both laboratories is further supported by the Excellence Cluster Cardio-Pulmonary System (ECCPS), the LOEWE/UGMLC program and [SFB/TRR81] NIH [R01 DK073639 to E.B.]; CCFA [SRA 2737]. Funding for open access charge: DFG.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871745733&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871745733&partnerID=8YFLogxK
U2 - 10.1093/nar/gks916
DO - 10.1093/nar/gks916
M3 - Article
C2 - 23087373
AN - SCOPUS:84871745733
SN - 0305-1048
VL - 41
SP - 90
EP - 109
JO - Nucleic acids research
JF - Nucleic acids research
IS - 1
ER -