The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation
The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation
复制标题
DOI：
10.1074/jbc.m004376200
复制
发表时间：
2001-02-02
影响因子：
4.8
通讯作者：
Kracht, M
中科院分区：
文献类型：
--
作者：
Holtmann, H;Enninga, J;Kracht, M
以趋化细胞因子白细胞介素-8（IL-8）的表达为模型，研究了炎症反应期间爆发性基因诱导的机制。最近，我们发现NF-κ B和c-Jun N-末端蛋白激酶（JNK）的协同激活是强IL-8转录所必需的，而p38 MAP激酶（MAPK）通路稳定IL-8 mRNA。目前还不清楚这些通路如何与IL-1受体（IL-8的重要生理诱导物）偶联。在HeLa细胞中，MAP激酶（MAPKKK）TAK 1及其共激活因子TAB 1的表达激活了所有三种途径，足以诱导IL-8形成、NF-κ B + JNK 2介导的最小IL-8启动子转录以及p38 MAPK介导的含有IL-8衍生调控mRNA序列的报告mRNA稳定化。TAK 1激酶失活突变体的表达在很大程度上阻断了IL-1诱导的转录和mRNA稳定，以及内源性IL-8的形成。缺少TAK 1结合结构域的截短TAB 1或含有TAK 1自身抑制结构域的TAK 1衍生肽也有效抑制。这些数据表明，先前描述的IL-8诱导的三途径模型在响应生理刺激IL-1时是有效的，并且MAPKKK TAK 1将IL-1受体偶联到由三种途径介导的转录和RNA靶向机制。
Mechanisms of fulminant gene induction during an inflammatory response were investigated using expression of the chemoattractant cytokine interleukin-8 (IL-8) as a model. Recently we found that coordinate activation ofNF-kappaB and c-Jun N-terminal protein kinase (JNK) is required for strong IL-8 transcription, whereas the p38 MAP kinase (MAPK) pathway stabilizes the IL-8 mRNA It is unclear how these pathways are coupled to the receptor for IL-1, an important physiological inducer of IL-8. Expression of the MAP kinase kinase kinase (MAPKKK) TAK1 together with its coactivator TAB1 in HeLa cells activated all three pathways and was sufficient to induce IL-8 formation, NF-kappaB + JNK2-mediated transcription from a minimal IL-8 promoter, and p38 MAPK-mediated stabilization of a reporter mRNA containing IL-8-derived regulatory mRNA sequences. Expression of a kinase-inactive mutant of TAK1 largely blocked IL-1-induced transcription and mRNA stabilization, as well as formation of endogenous IL-8. Truncated TAB1, lacking the TAK1 binding domain, or a TAK1-derived peptide containing a TAK1 autoinhibitory domain were also efficient in inhibition. These data indicate that the previously described three-pathway model of IL-8 induction is operative in response to a physiological stimulus, IL-1, and that the MAPKKK TAK1 couples the IL-1 receptor to both transcriptional and RNA-targeted mechanisms mediated by the three pathways.