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.
Highlights
The transcription factor NF-B plays an important role in a number of fundamental biological processes including cell cycle, proliferation, differentiation and cell death [1]
Our analyses demonstrate that p50 serine 80 (S80) phosphorylation predominantly regulates transcription through p50:p65 heterodimers and shows that p50 phosphorylation may function in trans to inhibit gene transcription
Our analysis demonstrates that S80 phosphorylation reduces the affinity of p50 for B sites that have an adenine at the −1 position, limiting the expression of genes regulated by these binding sites
Summary
The transcription factor NF-B plays an important role in a number of fundamental biological processes including cell cycle, proliferation, differentiation and cell death [1]. The NFB transcription factor family is comprised of five structurally related subunits: p65 (RelA), RelB, c-Rel, p50 and p52. The p50 and p52 subunits are generated from the limited proteasomal processing of the precursor proteins p105 and p100 respectively, and lack the transactivation domain (TAD) found in the C terminal regions of the p65, c-Rel and RelB subunits. All NF-B subunits contain a highly conserved Rel homology domain (RHD) which facilitates dimerisation and DNA binding. P50 homodimers may function as transcriptional repressors by competing with TAD containing NF-B dimers for the same DNA binding sites in target gene promoters [3]
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