Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription.
Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB (NF-kappaB) 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-kappaB in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-kappaB (p65 and p50) and synergistically coactivates NF-kappaB-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-kappaB 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-kappaB-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.
Hassa
Paul O
PO
Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Haenni
Sandra S
SS
Buerki
Christine
C
Meier
Nadja I
NI
Lane
William S
WS
Owen
Heather
H
Gersbach
Monika
M
Imhof
Ralph
R
Hottiger
Michael O
MO
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000502:physiology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000032:analysis / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000494:pharmacology / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D054426:Chemokine CXCL2; D018925:Chemokines; D051548:Histone Acetyltransferases; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C404915:Cxcl2 protein, mouse; C496317:Nos2 protein, mouse; C494364:Crebbp protein, mouse; C499321:Parp1 protein, mouse