Acetylation of Poly(ADP-ribose) Polymerase-1 by p300/CREB-binding Protein Regulates Coactivation of NF-κB-dependent Transcription

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor B (NF-B) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders. We recently presented evidence that PARP-1 can act as a promoter-specific coactivator of NF-B in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-B (p65 and p50) and synergistically coactivates NF-B-dependent transcription. Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation. Furthermore, acetylation of PARP-1 at these residues is required for the interaction of PARP-1 with p50 and synergistic coactivation of NF-B by p300 and the Mediator complex in response to inflammatory stimuli. PARP-1 physically interacts with the Mediator. Interestingly, PARP-1 interacts in vivo with histone deacetylases (HDACs) 1-3 but not with HDACs 4 -6 and might be deacetylated in vivo by HDACs 1-3. Thus, acetylation of PARP-1 by p300/CREB-binding protein plays an important regulatory role in NF-B-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.Nuclear factor B (NF-B) is a widely expressed transcription factor of particular importance to the regulation of cells of the immune system (1). NF-B encompasses a family of inducible transcription factors including RelA/p65, RelB, c-Rel, p50, and p52 (1). These proteins share a conserved 300-amino acid region within their amino termini, designated Rel-homology domain (RHD). This domain is responsible for dimerization, nuclear translocation, DNA binding, and interaction with heterologous transcription factors (1). NF-B is composed of homo-or heterodimers with a range of DNA binding and activation potentials. The most abundant and best-studied form of NF-B in cells is a heterodimer consisting of the two subunits, p50 (NF-B1) and p65 (RelA). NF-B plays a key role in the regulation of many genes involved in mammalian immune and inflammatory responses, apoptosis, cell proliferation, and differentiation (1, 2). NF-B has additionally been associated with neurodegenerative processes and cancer (3, 4). In unstimulated cells, NF-B is sequestered in the cytoplasm as an inactive transcription factor complex by its physical association with one of several inhibitors of NF-B (IBs) 2 (5). Treatment of cells with extracellular stimuli including cytokines, bacterial lipopolysaccharides (LPS), phorbol esters, or potent oxidants leads to rapid phosphorylation of IB␣, which results in ubiquitination of IB␣ and subsequent degradation by the 26 S proteasome (4, 5). Dissociation of NF-B unmasks the nuclear localization sequences of p65 and p50 subunits, which leads to nuclear translocation and binding of NF-B to specific B consensus sequences in the chromatin and activation of specific subsets of genes (3).NF-B-dependent gene expression requires growing families of transcriptional coactivators (6, 7). The two key coactivators of NF-B, histone acetyltransferases p300 and its homo...

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…As a regulator of gene expression, PARP-1 seems to play a critical role in both these processes. Thus, PARP-1 contributes to NF-B activation in the inflammatory response, provoking CREB binding protein recruitment independent of poly[ADP]-ribosylation (Hassa et al, 2005). In contrast, PARP-1 enzymatic activity is need for the recruitment of coactivators to Elk-1 and Hes-1 during neuronal activation and neurogenesis, respectively (Ju et al, 2004;Cohen-Armon et al, 2007).…”

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…In contrast, in a transient assay, over expression of PARP1 was found to repress the transcription of genes containing the M-CAT sites, again suggesting that PARP1 has a dual role in gene expression, activation followed by repression, depending upon the degree of PARP activation [107]. Recent studies have also shown that PARP1 is a target of acetylation and decatylation by p300/pCAF and class-I HDACs, respectively, but not by the class-II HDACs [142]. Acetylation of PARP1 has been shown to stabilize its interaction with other partner proteins, e.g., NFkB and TEF1 (unpublished observation), leading to activation of their target genes, whereas the opposite is true for deacetylation of PARP1 by class-I HDACs [142].…”

“…Recent studies have also shown that PARP1 is a target of acetylation and decatylation by p300/pCAF and class-I HDACs, respectively, but not by the class-II HDACs [142]. Acetylation of PARP1 has been shown to stabilize its interaction with other partner proteins, e.g., NFkB and TEF1 (unpublished observation), leading to activation of their target genes, whereas the opposite is true for deacetylation of PARP1 by class-I HDACs [142]. In the context of the effect of TSA on αMHC gene induction, it is therefore possible that some effects of the class-I HDAC inhibition by TSA could be mediated by acetylation of PARP1, resulting in de-repression of the transcriptional activity of the TEF1/PARP1 complex.…”

5-Aminoisoquinolinone Reduces the Expression of Vascular Endothelial Growth Factor-C via the Nuclear Factor-kappa B Signaling Pathway in CT26 Cells

“…PARP-1 has been reported to be a co-activator of NF-kB in many inflammatory disorders (Pétrilli et al, 2004;Zheng et al, 2004). Indeed, it has been proposed that acetylation of PARP by p300/CREBbinding protein plays an essential regulatory role in NFkB-dependent transcription gene expression (Hassa et al, 2005). A series of evidences have shown that NF-kB binds to an NF-kB sequence in the VEGF-C promoter (Chilov et al, 1997;Zhang et al, 1997).…”