Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells
Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells
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DOI：
10.1073/pnas.1418399111
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发表时间：
2014-12-09
影响因子：
11.1
通讯作者：
Cohen, Philip
中科院分区：
文献类型：
--
作者：
Lopez-Pelaez, Marta;Lamont, Douglas J.;Cohen, Philip
人浆细胞样树突细胞系Gen2.2中IFN调节因子5（IRF 5）的siRNA敲低阻止了由化合物CL 097（Toll样受体7（TLR 7）的配体）诱导的IFN α产生。CL 097还刺激IRF 5在Ser 462处的磷酸化，并刺激野生型IRF 5的核转位，但不刺激IRF 5 [Ser 462 Ala]突变体。CL 097刺激的IRF 5在Ser 462的磷酸化及其核转位通过蛋白激酶IKK β的药理学抑制或IKK β或其“上游”激活剂（蛋白激酶TAK 1）的siRNA敲低来阻止。在用TLR 7激动剂化合物R848或核苷酸寡聚化结构域1（NOD 1）激动剂KF-1B刺激的鼠巨噬细胞系中获得了类似的结果。IKK β在体外使IRF 5的Ser 462磷酸化，并诱导野生型IRF 5的二聚化，但不诱导IRF 5 [S462 A]突变体。这些发现表明IKK β激活先天免疫系统的两个“主”转录因子IRF 5和NF-κ B。
The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFN alpha 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 beta or the siRNA knockdown of IKK beta 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 beta 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 beta activates two "master" transcription factors of the innate immune system, IRF5 and NF-kappa B.