Lys<sup>48sup>-linked TAK1 polyubiquitination at lysine-72 downregulates TNF伪-induced NF-魏B activation via mediating TAK1 degradation
- 作者：Yihui Fan<sup>asup><sup> ; sup><sup>1sup> ; Yi Shi<sup>bsup><sup> ; sup><sup>1sup> ; Shangfeng Liu<sup>csup><sup> ; sup><sup>dsup><sup> ; sup><sup>1sup> ; Renfang Mao<sup>esup> ; Lei An<sup>fsup> ; Yanling Zhao<sup>asup> ; Hong Zhang<sup>esup><sup> ; sup><sup>fsup> ; Fuchun Zhang<sup>gsup> ; Guotong Xu<sup>dsup><sup> ; sup><sup>hsup><sup> ; sup><sup>gtxu@tongji.edu.cnsup> ; Jun Qin<sup>bsup><sup> ; sup><sup>jqin@bcm.edusup> ; Jianhua Yang<sup>asup><sup> ; sup><sup>jianhuay@bcm.edusup>
- 关键词：TNF伪 ; TAK1 ; Lys48-linked polyubiquitination ; Degradation
- 刊名：Cellular Signalling
- 出版年：2012
- 期刊代码：42_08986568
- 类别：bio
- 出版时间：July, 2012
- 卷：24
- 期：7
- 页码：1381-1389
- 文件大小：1420 K
摘要
Protein kinases are important regulators of intracellular signal transduction pathways and play critical roles in diverse cellular processes. TAK1, a member of the MAPKKK family, is essential for TNF伪-induced NF-魏B activation. Phosphorylation and Lys<sup>63sup>-linked polyubiquitination (polyUb) of TAK1 are critical for its activation. However, whether TAK1 is regulated by polyubiquitination-mediated protein degradation after its activation remains unknown. Here we report that TNF伪 induces TAK1 Lys<sup>48sup> linked polyubiquitination and degradation at the later time course. Furthermore, we provide direct evidence that TAK1 is modified by Lys<sup>48sup>-linked polyubiquitination at lysine-72 by mass spectrometry. A K72R point mutation on TAK1 abolishes TAK1 Lys<sup>48sup>-linked polyubiquitination and enhances TAK1/TAB1 co-overexpression-induced NF-魏B activation. As expected, TAK1 K72R mutation inhibits TNF伪-induced Lys<sup>48sup>-linked TAK1 polyubiquitination and degradation. TAK1 K72R mutant prolongs TNF伪-induced NF-魏B activation and enhances TNF伪-induced IL-6 gene expression. Our findings demonstrate that TNF伪 induces Lys<sup>48sup>-linked polyubiquitination of TAK1 at lysine-72 and this polyubiquitination-mediated TAK1 degradation plays a critical role in the downregulation of TNF伪-induced NF-魏B activation.