Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NFκB activation
Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NFκB activation
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DOI：
10.1074/jbc.m706931200
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发表时间：
2008-05-23
影响因子：
4.8
通讯作者：
Li, Xiaoxia
中科院分区：
文献类型：
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作者：
Xiao, Hui;Qian, Wen;Li, Xiaoxia
IL-1受体相关激酶（IRAK）在白介素-1 （IL-1）刺激下被磷酸化、泛素化和降解。在这项研究中，我们发现在IL-1诱导下，IRAK可以通过Lys-48和lys -63连接的多泛素链被泛素化。Pellino 3b是环样基序泛素蛋白连接酶，可促进IRAK上lys -63连接的多泛素化。Pellino 3b介导的Lys-63-linked IRAK多泛素化与Lys-48- linked IRAK多泛素化竞争相同的泛素化位点，IRAK的Lys-134，从而阻断il -1诱导的IRAK降解。重要的是，Pellino 3b对IL-1诱导的IRAK降解的负面影响与Pellino 3b对IL-1诱导的TAK1依赖通路的抑制作用相关，这表明IRAK降解在IL-1诱导的TAK1激活中具有积极作用。综上所述，我们的研究结果表明Pellino 3b通过其泛素蛋白连接酶活性调节IRAK降解，从而作为IL-1信号传导的负调节因子。
IL-1 receptor-associated kinase (IRAK) is phosphorylated, ubiquitinated, and degraded upon interleukin-1 (IL-1) stimulation. In this study, we showed that IRAK can be ubiquitinated through both Lys-48- and Lys-63-linked polyubiquitin chains upon IL-1 induction. Pellino 3b is the RING-like motif ubiquitin protein ligase that promotes the Lys-63-linked polyubiquitination on IRAK. Pellino 3b-mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48- linked IRAK polyubiquitination for the same ubiquitination site, Lys-134 of IRAK, thereby blocking IL-1-induced IRAK degradation. Importantly, the negative impact of Pellino 3b on IL-1-induced IRAK degradation correlated with the inhibitory effect of Pellino 3b on the IL-1-induced TAK1-dependent pathway, suggesting that a positive role of IRAK degradation in IL-1 induced TAK1 activation. Taken together, our results suggest that Pellino 3b acts as a negative regulator for IL-1 signaling by regulating IRAK degradation through its ubiquitin protein ligase activity.