AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3.
AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3.
复制标题
DOI：
10.1172/jci17790
复制
发表时间：
2003-06
期刊：
影响因子：
--
通讯作者：
Rong Zhang;Xiangrong He;Weiming Liu;Meng Lu;J. Hsieh;W. Min
中科院分区：
文献类型：
--
作者：
Rong Zhang;Xiangrong He;Weiming Liu;Meng Lu;J. Hsieh;W. Min
TNF-α通过从凋亡信号调节激酶1（ASK 1）中解离14-3-3来部分激活ASK 1。在本研究中，我们确定了一种新的Ras GTP酶激活蛋白（Ras GAP）作为ASK 1相互作用蛋白（AIP 1）。AIP 1通过N-末端C2结构域内的富含赖氨酸的簇结合到ASK 1的C-末端结构域。AIP 1通过N-末端和C-末端之间的分子内相互作用以闭合形式存在，并且TNF-α诱导AIP 1的解折叠，导致AIP 1与ASK 1的缔合。因此，含有C2和GAP结构域的AIP 1的N-末端组成型结合ASK 1，并促进14-3-3从ASK 1释放。与14-3-3相反，AIP 1优先结合去磷酸化的ASK 1。募集的AIP 1增强ASK 1诱导的JNK活化，并且AIP 1的ASK 1结合和差距活性对于AIP 1增强的ASK 1活化是关键的。此外，TNF诱导的ASK 1/JNK激活在AIP 1被RNA干扰敲低的细胞中显著减弱。这些数据表明，AIP 1通过促进抑制剂14-3-3从ASK 1解离来介导TNF-α诱导的ASK 1活化，这是TNF-α活化ASK 1的一种新机制。
TNF-alpha activates ASK1 in part by dissociating 14-3-3 from apoptosis signal-regulating kinase 1 (ASK1). In the present study, we identified a novel Ras GTPase-activating protein (Ras-GAP) as an ASK1-interacting protein (AIP1). AIP1 binds to the C-terminal domain of ASK1 via a lysine-rich cluster within the N-terminal C2 domain. AIP1 exists in a closed form through an intramolecular interaction between the N-terminus and the C-terminus, and TNF-alpha induces unfolding of AIP1 leading to association of AIP1 with ASK1. Thus, the N-terminus of AIP1 containing the C2 and GAP domains constitutively binds to ASK1 and facilitates the release of 14-3-3 from ASK1. In contrast to 14-3-3, AIP1 binds preferentially to dephosphorylated ASK1. Recruited AIP1 enhances ASK1-induced JNK activation, and the ASK1 binding and the GAP activity of AIP1 are critical for AIP1-enhanced ASK1 activation. Furthermore, TNF-induced ASK1/JNK activation is significantly blunted in cells where AIP1 is knocked down by RNA interference. These data suggest that AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of inhibitor 14-3-3 from ASK1, a novel mechanism by which TNF-alpha activates ASK1.