The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes
The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes
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DOI：
10.1016/s1097-2765(04)00236-9
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发表时间：
2004-05-07
期刊：
影响因子：
16
通讯作者：
Chen, ZJJ
中科院分区：
文献类型：
--
作者：
Sun, LJ;Deng, L;Chen, ZJJ
CARD结构域蛋白BCL 10和paracaspase MALT 1对于响应于T细胞受体（TCR）刺激的IkappaB激酶（IKK）和NF-κ B的活化是必需的。在这里，我们提出的证据表明，TRAF 6泛素连接酶和TAK 1蛋白激酶介导IKK激活BCL 10和MALT 1。RNAi介导的MALT 1、TAK 1、TRAF 6和TRAF 2沉默抑制T细胞中TCR依赖性IKK活化和白细胞介素-2产生。此外，我们在体外用纯化的MALT 1、TRAF 6、TAK 1蛋白和泛素化酶（包括Ubc 13/Uev 1A）重建了从BCL 10到IKK活化的通路。我们发现，BCL 10和MALT 1蛋白的一小部分形成高分子量的寡聚体。引人注目的是，只有这些寡聚体形式的BCL 10和MALT 1可以在体外激活IKK。MALT 1寡聚体与TRAF 6结合，诱导TRAF 6寡聚化，并激活TRAF 6的连接酶活性以多聚泛素化NEMO。这些结果揭示了寡聚化-->泛素化-->磷酸化级联反应，其在T淋巴细胞中的NF-κ B活化中达到高潮。
The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IkappaB kinase (IKK) and NF-kappaB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes.