期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：41
页码：14794-14799
DOI：10.1073/pnas.1410124111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTNF 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-{kappa}B 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 TNF-induced fibroblast migration. We show that the I{kappa}B kinase (IKK) phosphorylates RelB on serine 472 in response to TNF, 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-{kappa}B target gene expression and cellular response in response to TNF. TNF is a potent cytokine that plays a critical role in numerous cellular processes, particularly immune and inflammatory responses, programmed cell death, angiogenesis, and cell migration. Thus, understanding the molecular mechanisms that mediate TNF-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-{kappa}B avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNF treatment in fibroblasts, despite its TNF-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNF treatment. We identified the two kinases I{kappa}B kinase (IKK) and I{kappa}B kinase {beta} (IKK{beta}) as RelB interacting partners whose activation by TNF promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein I{kappa}B and binds to the promoter of critical migration-associated genes, such as the matrix metallopeptidase 3 (MMP3). Further, we show that RelB serine 472 phosphorylation status controls MMP3 expression and promigration activity downstream of TNF receptors. Our findings provide new insights into the regulation of RelB activity and reveal a novel link between selective NF-{kappa}B target gene expression and cellular response in response to TNF.
