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)

    Research output: Contribution to journalArticle

    37 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 - 2014

    Fingerprint

    Toll-Like Receptor 7
    Dimerization
    Myeloid Cells
    Protein Kinases
    Small Interfering RNA
    resiquimod
    Phosphorylation
    Cell Line
    Dendritic Cells
    Immune System
    Transcription Factors
    Nucleotides
    Macrophages
    Pharmacology
    Ligands

    Keywords

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

    Cite this

    @article{3368638104534bbbb76255eaf653ff6f,
    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 IFN{\ss} 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 IKK{\ss} or the siRNA knockdown of IKK{\ss} 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. IKK{\ss} phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKK{\ss} activates two {"}master{"} transcription factors of the innate immune system, IRF5 and NF-?B.",
    keywords = "IKK-BETA, Interferon-beta, IRF5, plasmacytoid dendritic cell, TLR7",
    author = "{Lopez Pelaez}, Marta and Lamont, {Douglas J.} and Mark Peggie and Natalia Shpiro and Gray, {Nathanael S.} and Philip Cohen",
    year = "2014",
    doi = "10.1073/pnas.1418399111",
    language = "English",
    volume = "111",
    pages = "17432--17437",
    journal = "Proceedings of the National Academy of Sciences",
    issn = "0027-8424",
    publisher = "National Academy of Sciences",
    number = "49",

    }

    Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. / Lopez Pelaez, Marta; Lamont, Douglas J.; Peggie, Mark; Shpiro, Natalia; Gray, Nathanael S.; Cohen, Philip (Lead / Corresponding author).

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 49, 2014, p. 17432-17437.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

    AU - Lopez Pelaez, Marta

    AU - Lamont, Douglas J.

    AU - Peggie, Mark

    AU - Shpiro, Natalia

    AU - Gray, Nathanael S.

    AU - Cohen, Philip

    PY - 2014

    Y1 - 2014

    N2 - 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.

    AB - 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.

    KW - IKK-BETA

    KW - Interferon-beta

    KW - IRF5

    KW - plasmacytoid dendritic cell

    KW - TLR7

    U2 - 10.1073/pnas.1418399111

    DO - 10.1073/pnas.1418399111

    M3 - Article

    VL - 111

    SP - 17432

    EP - 17437

    JO - Proceedings of the National Academy of Sciences

    JF - Proceedings of the National Academy of Sciences

    SN - 0027-8424

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    ER -