MEKK4 sequesters RIP2 to dictate NOD2 signal specificity.
MEKK4 sequesters RIP2 to dictate NOD2 signal specificity.
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MEKK4隔离器RIP2决定NOD2信号特异性。
DOI：
10.1016/j.cub.2008.07.084
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发表时间：
2008-09-23
期刊：
影响因子：
9.2
通讯作者：
Abbott, Derek W.
中科院分区：
文献类型：
--
作者：
Clark, Nivedita M.;Marinis, Jill M.;Cobb, Brian A.;Abbott, Derek W.
克罗恩病易感蛋白NOD2在细胞内暴露于细菌时协调信号反应。虽然已知NOD2可以激活NFκB，但关于NOD2如何协调NFκB、JNK和p38等信号通路以调节细胞因子反应的分子机制知之甚少。由于克罗恩病的特征之一是细胞因子对正常细菌菌群的反应改变，信号通路的耦合可能对克罗恩病的病理生理很重要。我们发现一个MAP3K， MEKK4，与RIP2结合，将RIP2从NOD2信号通路中隔离出来。MEKK4:RIP2复合物在暴露于NOD2激动剂MDP时解离，允许NOD2与RIP2结合并激活NFκB。因此，MEKK4通过隔离RIP2来抑制NOD2:RIP2复合物激活NFκB信号通路，并且克罗恩病相关的NOD2多态性不能与MEKK4竞争RIP2结合。最后，我们发现MEKK4有助于决定NOD2激活下游的信号特异性，因为在暴露于MDP的巨噬细胞中，MEKK4的敲低会导致NFκB活性增加，p38活性缺失以及对TLR2和TLR4激动剂的反应性降低。这些生化结果表明，MEKK4对nod2驱动的NFκB通路的基础抑制可能在克罗恩病的发病机制中起重要作用。
The Crohn’s Disease-susceptibility protein, NOD2, coordinates signaling responses upon intracellular exposure to bacteria. While NOD2 is known to activate NFκB, little is known about the molecular mechanisms by which NOD2 coordinates functionally separate signaling pathways such as NFκB, JNK and p38 to regulate cytokine responses. Since one of the characteristics of Crohn’s Disease is an altered cytokine response to normal bacterial flora, the coupling of signaling pathways could be important for Crohn’s Disease pathophysiology. We find that a MAP3K, MEKK4, binds to RIP2 to sequester RIP2 from the NOD2 signaling pathway. This MEKK4:RIP2 complex dissociates upon exposure to the NOD2 agonist, MDP, allowing NOD2 to bind to RIP2 and activate NFκB. MEKK4 thus sequesters RIP2 to inhibit the NOD2:RIP2 complex from activating NFκB signaling pathways, and Crohn’s Disease-associated NOD2 polymorphisms cannot compete with MEKK4 for RIP2 binding. Lastly, we find that MEKK4 helps dictate signal specificity downstream of NOD2 activation as knockdown of MEKK4 in macrophages exposed to MDP causes increased NFκB activity, absent p38 activity and hyporesponsiveness to TLR2 and TLR4 agonists. These biochemical findings suggest that basal inhibition of the NOD2-driven NFκB pathway by MEKK4 could be important in the pathogenesis of Crohn’s Disease.
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