Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
J Biol Chem. 2011 Oct 28;286(43):37147-57. doi: 10.1074/jbc.M111.263384. Epub 2011 Sep 6.
B-cell CLL/lymphoma 10 (BCL10) is crucial for the activation of NF-κB in numerous immune receptor signaling pathways, including the T-cell receptor (TCR) and B-cell receptor signaling pathways. However, the molecular mechanisms that lead to signal transduction from BCL10 to downstream NF-κB effector kinases, such as TAK1 and components of the IKK complex, are not entirely understood. Here we used a proteomic approach and identified the E3 ligase MIB2 as a novel component of the activated BCL10 complex. In vitro translation and pulldown assays suggest direct interaction between BCL10 and MIB2. Overexpression experiments show that MIB2 controls BCL10-mediated activation of NF-κB by promoting autoubiquitination and ubiquitination of IKKγ/NEMO, as well as recruitment and activation of TAK1. Knockdown of MIB2 inhibited BCL10-dependent NF-κB activation. Together, our results identify MIB2 as a novel component of the activated BCL10 signaling complex and a missing link in the BCL10-dependent NF-κB signaling pathway.
B 细胞慢性淋巴细胞白血病/淋巴瘤 10 基因（BCL10）在多种免疫受体信号通路中对 NF-κB 的激活至关重要，包括 T 细胞受体（TCR）和 B 细胞受体信号通路。然而，导致 BCL10 向下游 NF-κB 效应激酶（如 TAK1 和 IKK 复合物的组成部分）传递信号的分子机制尚不完全清楚。在这里，我们使用蛋白质组学方法鉴定出 E3 连接酶 MIB2 是激活的 BCL10 复合物的一个新成员。体外翻译和下拉实验表明 BCL10 和 MIB2 之间存在直接相互作用。过表达实验表明，MIB2 通过促进 IKKγ/NEMO 的自泛素化和泛素化以及 TAK1 的募集和激活来控制 BCL10 介导的 NF-κB 激活。MIB2 的敲低抑制了 BCL10 依赖性 NF-κB 激活。总之，我们的研究结果确定了 MIB2 是激活的 BCL10 信号复合物的一个新成员，也是 BCL10 依赖性 NF-κB 信号通路中的一个缺失环节。
