白细胞介素-1诱导的核因子κB和c-Jun氨基末端激酶（JNK）激活在白细胞介素-1受体相关激酶（IRAK）处出现分歧。
IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK).
作者信息
Li X, Commane M, Jiang Z, Stark G R
机构信息
Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
出版信息
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4461-5. doi: 10.1073/pnas.071054198. Epub 2001 Apr 3.
Abstract
Mutant I1A cells, lacking IL-1 receptor-associated kinase (IRAK) mRNA and protein, have been used to study the involvement of IRAK in NFkappaB and c-Jun N-terminal kinase (JNK) activation. A series of IRAK deletion constructs were expressed in I1A cells, which were then tested for their ability to respond to IL-1. Both the N-terminal death domain and the C-terminal region of IRAK are required for IL-1-induced NFkappaB and JNK activation, whereas the N-proximal undetermined domain is required for the activation of NFkappaB but not JNK. The phosphorylation and ubiquitination of IRAK deletion mutants correlate tightly with their ability to activate NFkappaB in response to IL-1, but IRAK can mediate IL-1-induced JNK activation without being phosphorylated. These studies reveal that the IL-1-induced signaling pathways leading to NFkappaB and JNK activation diverge either at IRAK or at a point nearer to the receptor.
摘要
缺乏白细胞介素-1受体相关激酶（IRAK）mRNA和蛋白质的突变I1A细胞已被用于研究IRAK在核因子κB（NFκB）和c-Jun氨基末端激酶（JNK）激活中的作用。一系列IRAK缺失构建体在I1A细胞中表达，然后测试它们对白细胞介素-1作出反应的能力。IRAK的N末端死亡结构域和C末端区域对于白细胞介素-1诱导的NFκB和JNK激活都是必需的，而靠近N端的未确定结构域对于NFκB的激活是必需的，但对JNK的激活不是必需的。IRAK缺失突变体的磷酸化和泛素化与其响应白细胞介素-1激活NFκB的能力紧密相关，但IRAK可以在不被磷酸化的情况下介导白细胞介素-1诱导的JNK激活。这些研究表明，导致NFκB和JNK激活的白细胞介素-1诱导信号通路在IRAK处或在更靠近受体的点处出现分歧。
相似文献
1
IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK).白细胞介素-1诱导的核因子κB和c-Jun氨基末端激酶（JNK）激活在白细胞介素-1受体相关激酶（IRAK）处出现分歧。
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4461-5. doi: 10.1073/pnas.071054198. Epub 2001 Apr 3.
2
IRAK and TAK1 are required for IL-18-mediated signaling.白细胞介素-18介导的信号传导需要白细胞介素-1受体相关激酶（IRAK）和转化生长因子β激活激酶1（TAK1）。
Eur J Immunol. 2001 Dec;31(12):3747-54. doi: 10.1002/1521-4141(200112)31:12<3747::aid-immu3747>3.0.co;2-e.
3
A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK).小鼠白细胞介素-1受体相关激酶-1（IRAK-1）的一种新型剪接变体可激活核因子-κB（NF-κB）和c-Jun氨基末端激酶（JNK）。
Biochem J. 2003 Feb 15;370(Pt 1):159-66. doi: 10.1042/BJ20021218.
4
IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase.白细胞介素-1受体相关激酶4：白细胞介素-1受体相关激酶家族的一个具有白细胞介素-1受体相关激酶活性的新成员。
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72. doi: 10.1073/pnas.082100399.
5
Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.白细胞介素-1（IL-1）受体相关激酶依赖性IL-1诱导的信号复合物在质膜处使TAK1和TAB2磷酸化，并在细胞质中激活TAK1。
Mol Cell Biol. 2002 Oct;22(20):7158-67. doi: 10.1128/MCB.22.20.7158-7167.2002.
6
Functional analysis of the interleukin-1-receptor-associated kinase (IRAK-1) in interleukin-1 beta-stimulated nuclear factor kappa B (NF-kappa B) pathway activation: IRAK-1 associates with the NF-kappa B essential modulator (NEMO) upon receptor stimulation.白细胞介素-1受体相关激酶（IRAK-1）在白细胞介素-1β刺激的核因子κB（NF-κB）信号通路激活中的功能分析：在受体刺激后，IRAK-1与NF-κB必需调节因子（NEMO）相互作用。
Biochem J. 2001 Oct 15;359(Pt 2):403-10. doi: 10.1042/0264-6021:3590403.
7
Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR .聚肌胞苷酸（Poly(I-C)）诱导的Toll样受体3（TLR3）介导的核因子κB（NFκB）和丝裂原活化蛋白激酶（MAP激酶）激活是通过一条不依赖白介素-1受体相关激酶（IRAK）的途径，该途径利用信号转导成分TLR3-肿瘤坏死因子受体相关因子6（TRAF6）-转化生长因子β激活激酶1（TAK1）-TAK1结合蛋白2（TAB2）-蛋白激酶R（PKR）。
J Biol Chem. 2003 May 9;278(19):16713-9. doi: 10.1074/jbc.M300562200. Epub 2003 Feb 27.
8
Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production.白细胞介素（IL）-1受体相关激酶（IRAK）对多种IL-1信号通路的最佳诱导及IL-6产生的需求。
J Exp Med. 1998 Jun 15;187(12):2073-9. doi: 10.1084/jem.187.12.2073.
9
Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activity.白细胞介素-1受体相关激酶（IRAK）表达对白细胞介素-1信号传导的影响与其激酶活性无关。
FEBS Lett. 1999 Apr 1;448(1):81-5. doi: 10.1016/s0014-5793(99)00322-1.
10
Tumor necrosis factor (TNF) receptor 1 signaling downstream of TNF receptor-associated factor 2. Nuclear factor kappaB (NFkappaB)-inducing kinase requirement for activation of activating protein 1 and NFkappaB but not of c-Jun N-terminal kinase/stress-activated protein kinase.肿瘤坏死因子（TNF）受体相关因子2下游的肿瘤坏死因子（TNF）受体1信号传导。激活蛋白1和核因子κB（NFκB）激活对核因子κB诱导激酶的需求，但对c-Jun氨基末端激酶/应激激活蛋白激酶的激活无此需求。
J Biol Chem. 1997 Oct 17;272(42):26079-82. doi: 10.1074/jbc.272.42.26079.
引用本文的文献
1
Targeting cytokine and chemokine signaling pathways for cancer therapy.针对细胞因子和趋化因子信号通路的癌症治疗。
Signal Transduct Target Ther. 2024 Jul 22;9(1):176. doi: 10.1038/s41392-024-01868-3.
2
The IRAK-M death domain: a tale of three surfaces.白细胞介素-1受体相关激酶M死亡结构域：关于三个表面的故事
Front Mol Biosci. 2024 Jan 10;10:1265455. doi: 10.3389/fmolb.2023.1265455. eCollection 2023.
3
IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies.IRAK-4 抑制：emavusertib 治疗淋巴和髓系恶性肿瘤。
Front Immunol. 2023 Oct 26;14:1239082. doi: 10.3389/fimmu.2023.1239082. eCollection 2023.
4
IL-1 in Abdominal Aortic Aneurysms.腹主动脉瘤中的白细胞介素-1
J Cell Immunol. 2023;5(2):22-31. doi: 10.33696/immunology.5.163.
5
LXR agonist inhibits inflammation through regulating MyD88 mRNA alternative splicing.肝脏X受体激动剂通过调节髓样分化因子88（MyD88）mRNA可变剪接来抑制炎症。
Front Pharmacol. 2022 Oct 14;13:973612. doi: 10.3389/fphar.2022.973612. eCollection 2022.
6
Anti-NLRP3 Inflammasome Natural Compounds: An Update.抗NLRP3炎性小体的天然化合物：最新进展
Biomedicines. 2021 Feb 1;9(2):136. doi: 10.3390/biomedicines9020136.
7
Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?泛素化对核因子κB信号通路的调控：头颈鳞状细胞癌的潜在治疗靶点？
Cancers (Basel). 2020 Oct 7;12(10):2877. doi: 10.3390/cancers12102877.
8
S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1.S100A14 通过降解 IRAK1 抑制 NF-κB 信号通路从而抑制鼻咽癌的转移。
Oncogene. 2020 Jul;39(30):5307-5322. doi: 10.1038/s41388-020-1363-8. Epub 2020 Jun 17.
9
Molecular Dysfunction and Phenotypic Derangement in Diabetic Cardiomyopathy.糖尿病心肌病中的分子功能障碍和表型紊乱。
Int J Mol Sci. 2019 Jul 2;20(13):3264. doi: 10.3390/ijms20133264.
10
Deletion of interleukin 1 receptor-associated kinase 1 () improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.白细胞介素1受体相关激酶1（）的缺失主要通过提高骨骼肌中的胰岛素敏感性来改善葡萄糖耐量。
J Biol Chem. 2017 Jul 21;292(29):12339-12350. doi: 10.1074/jbc.M117.779108. Epub 2017 Jun 1.
本文引用的文献
1
Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation.IKK1和IKK2双缺陷小鼠中完全缺乏核因子κB活性：神经管形成中的额外缺陷。
Genes Dev. 2000 Jul 15;14(14):1729-33.
2
TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.TAB2是一种新型衔接蛋白，在白细胞介素-1信号转导途径中，通过将TAK1与TRAF6连接，介导TAK1丝裂原活化蛋白激酶激酶激酶（MAPKKK）的激活。
Mol Cell. 2000 Apr;5(4):649-58. doi: 10.1016/s1097-2765(00)80244-0.
3
Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.Tollip是白细胞介素-1受体相关激酶（IL-1RI）通路的一个新组分，它将白细胞介素-1受体相关激酶（IRAK）与白细胞介素-1受体连接起来。
Nat Cell Biol. 2000 Jun;2(6):346-51. doi: 10.1038/35014038.
4
Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice.NEMO/IKKγ缺陷小鼠中严重的肝脏变性和NF-κB激活缺失。
Genes Dev. 2000 Apr 1;14(7):854-62.
5
Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit.响应白细胞介素-1时磷脂酰肌醇3-激酶的激活导致NF-κB p65/RelA亚基的磷酸化和激活。
Mol Cell Biol. 1999 Jul;19(7):4798-805. doi: 10.1128/MCB.19.7.4798.
6
Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase.对白细胞介素-1（IL-1）无反应的突变细胞揭示了IL-1受体相关激酶的新作用。
Mol Cell Biol. 1999 Jul;19(7):4643-52. doi: 10.1128/MCB.19.7.4643.
7
IKK1-deficient mice exhibit abnormal development of skin and skeleton.IKK1基因缺陷的小鼠表现出皮肤和骨骼发育异常。
Genes Dev. 1999 May 15;13(10):1322-8. doi: 10.1101/gad.13.10.1322.
8
TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling.肿瘤坏死因子受体相关因子6（TRAF6）缺陷会导致骨硬化以及白细胞介素-1、CD40和脂多糖信号传导缺陷。
Genes Dev. 1999 Apr 15;13(8):1015-24. doi: 10.1101/gad.13.8.1015.
9
Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase.缺乏IκB激酶α亚基的小鼠中形态发生异常但IKK激活完整。
Science. 1999 Apr 9;284(5412):316-20. doi: 10.1126/science.284.5412.316.
10
The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway.激酶TAK1可激活IL-1信号通路中的NIK-IκB以及丝裂原活化蛋白激酶级联反应。
Nature. 1999 Mar 18;398(6724):252-6. doi: 10.1038/18465.
Zotero 插件