Smith, E. L., Somma, D., Kerrigan, D., McIntyre, Z., Cole, J. J., Liang, K. L., Kiely, P. A., Keeshan, K. and Carmody, R. J. (2019) The regulation of sequence specific NF-ĸB DNA binding and transcription by IKKβ Phosphorylation of NF-ĸB p50 at Serine 80. Nucleic Acids Research, 47(21), pp. 11151-11161. (doi: 10.1093/nar/gkz873) (PMID:31598684) (PMCID:PMC6868378)
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Abstract
Phosphorylation of the NF-κB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-κB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNFα inducible expression of a subset of NF-κB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-κB binding (κB) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at κB sites with an adenine at the −1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF-κB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific κB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses.
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