IKKβ是一种引发炎症的IRF5激酶。
IKKβ is an IRF5 kinase that instigates inflammation.
作者信息
Ren Junyao, Chen Xiang, Chen Zhijian J
机构信息
Department of Molecular Biology and.
Department of Molecular Biology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
出版信息
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17438-43. doi: 10.1073/pnas.1418516111. Epub 2014 Oct 17.
Abstract
The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKKβ phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll-like receptors and retinoic acid-inducible gene I-like receptors. IKKβ phosphorylates mouse IRF5 at specific residues, including serine 445 (S446 in human IRF5 isoform 1), as evidenced by mass spectrometry analysis and detection with a phosphospecific antibody. Recombinant IKKβ phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production. Depletion or pharmacologic inhibition of IKKβ prevented IRF5 phosphorylation. These results indicate that IKKβ is an IRF5 kinase that instigates inflammation.
摘要
转录因子干扰素调节因子5（IRF5）对于炎性细胞因子的诱导至关重要，但其激活机制尚未完全明确。在此，我们提供证据表明，激酶IKKβ在多种炎性信号通路受到刺激时，会磷酸化并激活IRF5，这些通路包括源自Toll样受体和视黄酸诱导基因I样受体的信号通路。通过质谱分析和磷酸化特异性抗体检测证实，IKKβ会在特定残基处磷酸化小鼠IRF5，包括丝氨酸445（人IRF5亚型1中的S446）。重组IKKβ在体外可使IRF5的丝氨酸445位点磷酸化，该丝氨酸的点突变会消除IRF5的激活及细胞因子产生。IKKβ的缺失或药物抑制可阻止IRF5的磷酸化。这些结果表明，IKKβ是一种引发炎症的IRF5激酶。
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本文引用的文献
1
Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells.蛋白激酶IKKβ催化的IRF5在丝氨酸462处的磷酸化诱导其在髓系细胞中的二聚化和核转位。
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17432-7. doi: 10.1073/pnas.1418399111. Epub 2014 Oct 17.
2
IRF5-mediated signaling and implications for SLE.IRF5 介导的信号转导及其对 SLE 的影响。
Clin Immunol. 2014 Aug;153(2):343-52. doi: 10.1016/j.clim.2014.06.001. Epub 2014 Jun 10.
3
The IRF family transcription factors at the interface of innate and adaptive immune responses.处于固有免疫和适应性免疫反应交界的IRF家族转录因子。
Cold Spring Harb Symp Quant Biol. 2013;78:105-16. doi: 10.1101/sqb.2013.78.020321. Epub 2013 Oct 3.
4
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PLoS Pathog. 2013 Jan;9(1):e1003118. doi: 10.1371/journal.ppat.1003118. Epub 2013 Jan 3.
5
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Science. 2013 Feb 15;339(6121):786-91. doi: 10.1126/science.1232458. Epub 2012 Dec 20.
6
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Science. 2013 Feb 15;339(6121):826-30. doi: 10.1126/science.1229963. Epub 2012 Dec 20.
7
IKK biology.IKK 生物学。
Immunol Rev. 2012 Mar;246(1):239-53. doi: 10.1111/j.1600-065X.2012.01107.x.
8
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9
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10
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