Details

Autor(en) / Beteiligte

• Lopez-Pelaez, Marta
• Lamont, Douglas J.
• Peggie, Mark
• Shpiro, Natalia
• Gray, Nathanael S.
• Cohen, Philip

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-12, Vol.111 (49), p.17432-17437

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Significance NF-κB and IFN Regulatory Factor 5 (IRF5) are required for the transcription of many proinflammatory cytokines in myeloid cells. The protein kinase IKKβ is the major activator of NF-κB but how IRF5 is activated has been unclear. This paper demonstrates that IKKβ also activates IRF5 by catalyzing the phosphorylation of Ser462. The phosphorylation of this serine induces the dimerization of IRF5 and its translocation to the nucleus. The activation of the master transcription factors of the innate immune system by the same protein kinase provides a mechanism for the coordinated control of IRF5 and NF-κB in response to inflammatory stimuli. 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.