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

Item Type:Article
Title:IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors
Creators Name:Authier, H. and Billot, K. and Derudder, E. and Bordereaux, D. and Riviere, P. and Rodrigues-Ferreira, S. and Nahmias, C. and Baud, V.
Abstract:TNF{alpha} 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{alpha}-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{alpha} treatment in fibroblasts, despite its TNF{alpha}-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNF{alpha} treatment. We identified the two kinases I{kappa}B kinase {alpha} (IKK{alpha}) and I{kappa}B kinase {beta} (IKK{beta}) as RelB interacting partners whose activation by TNF{alpha} promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein IκB{alpha} 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-κB target gene expression and cellular response in response to TNF{alpha}.
Keywords:TNFalpha, NF-kappaB, Metalloproteinase, Posttranslational Modification, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:111
Number:41
Page Range:14794-14799
Date:14 October 2014
Official Publication:https://doi.org/10.1073/pnas.1410124111
PubMed:View item in PubMed

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