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

doi:10.1073/pnas.1418399111

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 journal › Article › peer-review

86 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 language	English
Pages (from-to)	17432-17437
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	49
Early online date	17 Oct 2014
DOIs	https://doi.org/10.1073/pnas.1418399111
Publication status	Published - 9 Dec 2014

Keywords

IKK-BETA
Interferon-beta
IRF5
plasmacytoid dendritic cell
TLR7

Access to Document

10.1073/pnas.1418399111

Elucidation of Molecular Mechanisms that Activate the MyD88 Signaling Network (Senior Investigator Award)
Cohen, P. (Investigator)
1/04/13 → 31/03/18
Project: Research
Characterisation of Signal Transduction Pathways that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases (Programme Grant)
Cohen, P. (Investigator)
Medical Research Council
1/04/13 → 31/03/18
Project: Research

Cohen, Philip
- MRC PPU - Research Professor of Enzymology
Person: Academic

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",

month = dec,

day = "9",

doi = "10.1073/pnas.1418399111",

language = "English",

volume = "111",

pages = "17432--17437",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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 et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 49, 09.12.2014, p. 17432-17437.

Research output: Contribution to journal › Article › peer-review

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 - 2014/12/9

Y1 - 2014/12/9

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

C2 - 25326418

SN - 0027-8424

VL - 111

SP - 17432

EP - 17437

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 49

ER -

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

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Keywords

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Projects

Elucidation of Molecular Mechanisms that Activate the MyD88 Signaling Network (Senior Investigator Award)

Characterisation of Signal Transduction Pathways that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases (Programme Grant)

Profiles

Cohen, Philip

Cite this