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Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNF?-induced NF-?B activation via mediating TAK1 degradation.


ABSTRACT: 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?-induced NF-?B activation. Phosphorylation and Lys(63)-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? induces TAK1 Lys(48) linked polyubiquitination and degradation at the later time course. Furthermore, we provide direct evidence that TAK1 is modified by Lys(48)-linked polyubiquitination at lysine-72 by mass spectrometry. A K72R point mutation on TAK1 abolishes TAK1 Lys(48)-linked polyubiquitination and enhances TAK1/TAB1 co-overexpression-induced NF-?B activation. As expected, TAK1 K72R mutation inhibits TNF?-induced Lys(48)-linked TAK1 polyubiquitination and degradation. TAK1 K72R mutant prolongs TNF?-induced NF-?B activation and enhances TNF?-induced IL-6 gene expression. Our findings demonstrate that TNF? induces Lys(48)-linked polyubiquitination of TAK1 at lysine-72 and this polyubiquitination-mediated TAK1 degradation plays a critical role in the downregulation of TNF?-induced NF-?B activation.

SUBMITTER: Fan Y 

PROVIDER: S-EPMC3580185 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNFα-induced NF-κB activation via mediating TAK1 degradation.

Fan Yihui Y   Shi Yi Y   Liu Shangfeng S   Mao Renfang R   An Lei L   Zhao Yanling Y   Zhang Hong H   Zhang Fuchun F   Xu Guotong G   Qin Jun J   Yang Jianhua J  

Cellular signalling 20120303 7


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 TNFα-induced NF-κB activation. Phosphorylation and Lys(63)-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 TNFα induces TAK1 Lys(48)  ...[more]

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