IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

Significance TNFα induces chemotaxis of inflammatory cells and fibroblasts, but little is known about the signaling mechanisms controlling this action. It is generally accepted that the avian reticuloendotheliosis viral oncogene (v-rel) related B (RelB) NF-κB subunit is not activated downstream of TNF receptors in fibroblasts. Here, we revealed an activating molecular mechanism leading to RelB transcriptional activation that is critical for the control of TNFα-induced fibroblast migration. We show that the IκB kinase (IKK) phosphorylates RelB on serine 472 in response to TNFα, leading RelB to bind to the promoter of critical migration-associated genes, such as the matrix metallopeptidase 3 (MMP3), thereby controlling MMP3 expression and promigration activity. These findings shed light on a crucial regulatory mechanism controlling selective NF-κB target gene expression and cellular response in response to TNFα.