title: IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors.
abstract: TNFα 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 TNFα-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-κB avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNFα treatment in fibroblasts, despite its TNFα-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNFα treatment. We identified the two kinases IκB kinase α (IKKα) and IκB kinase β (IKKβ) as RelB interacting partners whose activation by TNFα promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein IκBα 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 TNFα.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Hélène
authors.initials: H
authors.lastname: Authier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Katy
authors.initials: K
authors.lastname: Billot
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Derudder
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Didier
authors.initials: D
authors.lastname: Bordereaux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rivière
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rodrigues-Ferreira
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and.
authors.forename: Clara
authors.initials: C
authors.lastname: Nahmias
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; and veronique.baud@inserm.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB; D010768:Phosphoserine; D051550:I-kappa B Kinase; D019278:Matrix Metalloproteinase 3
keywords: NF-kappaB; TNFalpha; metalloproteinase; posttranslational modification