NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK.
Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-kappaB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-kappaB in suppressing the expression of anti-inflammatory or anti-tumor genes.
Liu
Guang-Hui
GH
Institute of Biophysics, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Beijing, PR China.
Qu
Jing
J
Shen
Xun
X
D000975:Antioxidants / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D050985:MafK Transcription Factor / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B; D020218:Response Elements; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
D000975:Antioxidants; D050882:CREB-Binding Protein; D006655:Histone Deacetylases; D050985:MafK Transcription Factor; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3