The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO
The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO
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DOI：
10.1016/j.cub.2004.12.032
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发表时间：
2004-12-29
期刊：
影响因子：
9.2
通讯作者：
Cantley, LC
中科院分区：
文献类型：
--
作者：
Abbott, DW;Wilkins, A;Cantley, LC
背景资料：克罗恩病是胃肠道的自身免疫性炎性疾病，其临床特征在于促炎性和抗炎性细胞因子信号传导网络的失调。克罗恩病蛋白NOD 2的功能突出了克罗恩病病理学的双相性质。NOD 2可以强烈激活和负性减弱NF-κ B信号传导。NOD 2的这种双重功能的生化机制是未知的。结果：我们证明，NOD 2的激活导致泛素化的NEMO，NF-κ B信号复合物的关键组成部分。这种泛素化是激动剂依赖性的，并且它不调节NEMO的蛋白体破坏。我们发现NEMO的NOD 2依赖性泛素化依赖于支架蛋白激酶RIP 2。克罗恩病相关的NOD 2多态性显示结合RIP 2的能力降低，这种结合RIP 2的能力降低与泛素化NEMO的能力降低相关。我们将NEMO泛素化位点映射到一个新的NEMO泛素化位点（赖氨酸285），并表明这种泛素化发生在体内。最后，我们表明，在功能上，RIP 2诱导的泛素化NEMO是至少部分负责RIP 2介导的NF-κ B activation.Conclusions：这些数据表明，这种新的模式的NF-κ B信号通路的调节可能是克罗恩病的发病机制的一个因素。
Background: Crohn's disease is an autoimmune inflammatory disorder of the gastrointestinal tract and is characterized clinically by dysregulation of both pro-inflammatory and anti-inflammatory cytokine signaling networks. The function of the Crohn's disease protein, NOD2, highlights the biphasic nature of the pathology of Crohn's disease. NOD2 can both strongly activate and negatively attenuate NF-kB signaling. The biochemical mechanism for this dual function of NOD2 is unknown.Results: We demonstrate that NOD2 activation leads to ubiquitinylation of NEMO, a key component of the NF- kB signaling complex. This ubiquitinylation is agonist dependant, and it does not regulate proteosomal destruction of NEMO. We show the NOD2-dependent ubiquitinylation of NEMO is dependent on the scaffolding protein kinase RIP2. Crohn's disease-associated polymorphisms of NOD2 show a decreased ability to bind RIP2, and this decreased ability to bind RIP2 correlates with a decreased ability to ubiquitinylate NEMO. We map the site of NEMO ubiquitinylation to a novel NEMO ubiquitinylation site (Lysine 285) and show that this ubiquityinylation occurs in vivo. Lastly, we show functionally that RIP2-induced ubiquitinylation of NEMO is at least in part responsible for RIP2-mediated NF-kB activation.Conclusions: These data suggest that this novel mode of regulation of the NF-kB signaling pathway could be a factor underlying the pathogenesis of Crohn's disease.