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首页> 外文期刊>Cellular Signalling >Lys ~(48)-linked TAK1 polyubiquitination at lysine-72 downregulates TNFα-induced NF-κB activation via mediating TAK1 degradation
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Lys ~(48)-linked TAK1 polyubiquitination at lysine-72 downregulates TNFα-induced NF-κB activation via mediating TAK1 degradation

机译：赖氨酸〜72上的赖氨酸〜（48）-连接的TAK1多聚泛素通过介导TAK1的降解下调TNFα诱导的NF-κB活化。

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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 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) 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-κB activation. As expected, TAK1 K72R mutation inhibits TNFα-induced Lys ~(48)-linked TAK1 polyubiquitination and degradation. TAK1 K72R mutant prolongs TNFα-induced NF-κB activation and enhances TNFα-induced IL-6 gene expression. Our findings demonstrate that TNFα induces Lys ~(48)-inked polyubiquitination of TAK1 at lysine-72 and this polyubiquitination-mediated TAK1 degradation plays a critical role in the downregulation of TNFα-induced NF-κB activation.
机译：蛋白激酶是细胞内信号转导途径的重要调节剂，并在各种细胞过程中发挥关键作用。 TAK1是MAPKKK家族的成员，对于TNFα诱导的NF-κB激活至关重要。 TAK1的磷酸化和与Lys〜（63）连接的多泛素化（polyUb）对于其激活至关重要。然而，TAK1激活后是否受多泛素介导的蛋白质降解调控。在这里我们报告TNFα诱导TAK1 Lys〜（48）连锁的泛素化和降解在以后的时间过程。此外，我们提供了直接的证据，表明TAK1被赖氨酸〜（48）-赖氨酸72处的多聚泛素化修饰。 TAK1上的一个K72R点突变消除了TAK1 Lys〜（48）-连接的多聚泛素化作用，并增强了TAK1 / TAB1共表达引起的NF-κB活化。如所预期的，TAK1 K72R突变抑制了TNFα诱导的Lys〜（48）连锁的TAK1多聚泛素化和降解。 TAK1 K72R突变体延长了TNFα诱导的NF-κB激活并增强了TNFα诱导的IL-6基因表达。我们的发现表明，TNFα在赖氨酸72诱导TAK1的Lys〜（48）介导的多泛素化，而这种多泛素介导的TAK1降解在TNFα诱导的NF-κB激活的下调中起关键作用。

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