TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains
TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains
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DOI：
10.1016/j.molcel.2004.08.008
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发表时间：
2004-08-27
期刊：
影响因子：
16
通讯作者：
Chen, ZJ
中科院分区：
文献类型：
--
作者：
Kanayama, A;Seth, RB;Chen, ZJ
核因子-kappaB和IKK的激活需要由TAK1和接头蛋白如Tab1、TAB2或Tab3组成的上游激酶复合体。TAK1又被TRAF6激活，TRAF6是一种环状结构域泛素连接酶，有助于合成赖氨酸63连接的多泛素链。在这里，我们提出的证据表明，Tab2和Tab3是受体，通过高度保守的锌指结构域优先与赖氨酸63连接的多泛素链结合。锌F结构域的突变取消了TAB2和TAB3结合多泛素链的能力，以及它们激活TAK1和IKK的能力。值得注意的是，用异源泛素结合区替换了锌F结构域，恢复了Tab2和Tab3激活TAK1和IKK的能力。我们还表明，TAB2在TNFpha刺激后与多泛素化的RIP结合。这些结果表明，多泛素结合域代表了一类新的信号域，通过非蛋白分解机制调节蛋白激酶的活性。
The activation of NF-kappaB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains. Here we present evidence that TAB2 and TAB3 are receptors that bind preferentially to lysine 63-linked polyubiquitin chains through a highly conserved zinc finger (ZnF) domain. Mutations of the ZnF domain abolish the ability of TAB2 and TAB3 to bind polyubiquitin chains, as well as their ability to activate TAK1 and IKK. Significantly, replacement of the ZnF domain with a heterologous ubiquitin binding domain restored the ability of TAB2 and TAB3 to activate TAK1 and IKK. We also show that TAB2 binds to polyubiquitinated RIP following TNFalpha stimulation. These results indicate that polyubiquitin binding domains represent a new class of signaling domains that regulate protein kinase activity through a nonproteolytic mechanism.