Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

Marta Lopez Pelaez, Douglas J. Lamont, Mark Peggie, Natalia Shpiro, Nathanael S. Gray, Philip Cohen (Lead / Corresponding author)

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    53 Citations (Scopus)

    Abstract

    The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNß 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 IKKß or the siRNA knockdown of IKKß 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. IKKß phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKß activates two "master" transcription factors of the innate immune system, IRF5 and NF-?B.
    Original languageEnglish
    Pages (from-to)17432-17437
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number49
    Early online date17 Oct 2014
    DOIs
    Publication statusPublished - 9 Dec 2014

    Keywords

    • IKK-BETA
    • Interferon-beta
    • IRF5
    • plasmacytoid dendritic cell
    • TLR7

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