TAK1 is a central mediator of NOD2 signaling in epidermal cells
TAK1 is a central mediator of NOD2 signaling in epidermal cells
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DOI：
10.1074/jbc.m704746200
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发表时间：
2008-01-04
影响因子：
4.8
通讯作者：
Ninomiya-Tsuji, Jun
中科院分区：
文献类型：
--
作者：
Kim, Jae-Young;Omori, Emily;Ninomiya-Tsuji, Jun
胞壁酰二肽 (MDP) 是源自共生菌和病原菌的肽聚糖部分，也是其细胞内传感器 NOD2 的配体。 NOD2 突变与克罗恩病高度相关，克罗恩病的特点是肠道炎症失调。然而，NOD2信号异常与炎症之间的联系机制尚未阐明。在这里，我们证明转化生长因子 β 激活激酶 1 (TAK1) 是 NOD2 信号转导的重要中间体。我们发现 TAK1 缺失完全消除了 MDP-NOD2 信号传导、NF-κ B 和 MAPK 的激活以及随后角质形成细胞中细胞因子/趋化因子的诱导。 NOD2 及其下游效应子 RICK 与 TAK1 相关并被激活。 TAK1 缺陷也会消除 MDP 诱导的 NOD2 表达。由于表皮特异性缺失 TAK1 的小鼠会出现严重的炎症状况，因此我们认为 TAK1 和 NOD2 信号传导对于维持皮肤的正常稳态非常重要，其消融可能会损害皮肤屏障功能，从而导致炎症。
Muramyl dipeptide (MDP) is a peptidoglycan moiety derived from commensal and pathogenic bacteria, and a ligand of its intracellular sensor NOD2. Mutations in NOD2 are highly associated with Crohn disease, which is characterized by dysregulated inflammation in the intestine. However, the mechanism linking abnormality of NOD2 signaling and inflammation has yet to be elucidated. Here we show that transforming growth factor beta-activated kinase 1 (TAK1) is an essential intermediate of NOD2 signaling. We found that TAK1 deletion completely abolished MDP-NOD2 signaling, activation of NF-kappa B and MAPKs, and subsequent induction of cytokines/chemokines in keratinocytes. NOD2 and its downstream effector RICK associated with and activated TAK1. TAK1 deficiency also abolished MDP-induced NOD2 expression. Because mice with epidermis-specific deletion of TAK1 develop severe inflammatory conditions, we propose that TAK1 and NOD2 signaling are important for maintaining normal homeostasis of the skin, and its ablation may impair the skin barrier function leading to inflammation.