ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways.
ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways.
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DOI：
10.1016/j.cub.2009.06.038
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发表时间：
2009-08-11
期刊：
影响因子：
--
通讯作者：
Abbott DW
中科院分区：
文献类型：
--
作者：
Tao M;Scacheri PC;Marinis JM;Harhaj EW;Matesic LE;Abbott DW
不能协调导致适当细胞因子应答的信号传导途径是炎性疾病如克罗恩病的发病机制的特征。克罗恩病易感性蛋白NOD 2有助于在细胞内暴露于细菌时协调细胞因子应答，并且NOD 2的这种信号协调部分地通过K63连接的多聚泛素链来实现，所述多聚泛素链产生用于信号传导复合物的支架的结合表面。在这项工作中，我们表明，NOD 2的信号伙伴，RIP 2，是直接K63多泛素化的ITCH，E3泛素连接酶，当失去遗传，导致广泛的炎症性疾病在粘膜表面。我们表明，ITCH是负责RIP 2多聚泛素化反应感染单核细胞增生症。我们进一步表明NOD 2可以结合多泛素化的RIP 2，而ITCH E3连接酶活性是NOD 2：RIP 2诱导的p38和JNK活化所必需的，ITCH抑制NOD 2：RIP 2诱导的NFκB活化。通过对经MDP处理的瘙痒−/−原代巨噬细胞的微阵列分析，可以在全基因组水平上独立地观察到这种效应。这些发现表明，ITCH有助于调节NOD 2依赖的信号转导通路，因此，可能参与NOD 2介导的炎症性疾病的发病机制。
The inability to coordinate the signaling pathways that lead to proper cytokine responses characterizes the pathogenesis of inflammatory diseases such as Crohn's Disease. The Crohn's Disease susceptibility protein, NOD2, helps coordinate cytokine responses upon intracellular exposure to bacteria, and this signal coordination by NOD2 is accomplished, in part, through K63-linked polyubiquitin chains that create binding surfaces for the scaffolding of signaling complexes. In this work, we show that the NOD2 signaling partner, RIP2, is directly K63 polyubiquitinated by ITCH, an E3 ubiquitin ligase which when lost genetically, causes widespread inflammatory disease at mucosal surfaces. We show that ITCH is responsible for RIP2 polyubiquitination in response to infection with listeria monocytogenes. We further show that NOD2 can bind polyubiquitinated RIP2, and while ITCH E3 ligase activity is required for optimal NOD2:RIP2-induced p38 and JNK activation, ITCH inhibits NOD2:RIP2-induced NFκB activation. This effect can be seen independently at the whole genome level by microarray analysis of MDP-treated Itch−/− primary macrophages. These findings suggest that ITCH helps regulate NOD2-dependent signal transduction pathways and as such, may be involved in the pathogenesis of NOD2-mediated inflammatory disease.
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