title: Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells.
abstract: The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNβ production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKKβ or the siRNA knockdown of IKKβ or its "upstream" activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKKβ phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKβ activates two "master" transcription factors of the innate immune system, IRF5 and NF-κB.
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, and.
authors.forename: Marta
authors.initials: M
authors.lastname: Lopez-Pelaez
authors.affiliation: College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom; and.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lamont
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Peggie
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, and.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shpiro
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, and p.cohen@dundee.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D012694:Serine / Q000737:chemistry; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D008024:Ligands; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D012694:Serine; D016899:Interferon-beta
keywords: IKKβ; IRF5; TLR7; interferon β; plasmacytoid dendritic cell