NDR1 protein kinase promotes IL-17-and TNF-α-mediated inflammation by competitively binding TRAF3
NDR1 protein kinase promotes IL-17-and TNF-α-mediated inflammation by competitively binding TRAF3
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DOI：
10.15252/embr.201642140
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发表时间：
2017-04-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Ma, Chunmei;Lin, Wenlong;Wang, Xiaojian
白细胞介素17（IL-17）是一种重要的组织炎症诱导因子，参与多种自身免疫性疾病。然而，其信号转导是如何调节的还不清楚。在此，我们报道了核Dbf 2相关激酶1（NDR 1）作为IL-17信号转导和IL-17诱导的炎症的正调节剂的功能。NDR 1缺陷或敲低抑制IL-17诱导的p38、ERK 1/2和p65的磷酸化以及趋化因子和细胞因子的表达，而NDR 1的过表达促进IL-17诱导的信号传导，而不依赖于其激酶活性。从机制上讲，NDR 1与TRAF 3相互作用并阻止其与IL-17 R结合，从而促进IL-17 R-Act 1-TRAF 6复合物的形成和下游信号传导。与此一致，IL-17诱导的炎症在NDR 1缺陷小鼠中显著减少，并且NDR 1缺陷显著保护小鼠免受MOG诱导的实验性自身免疫性脑脊髓炎（EAE）和2，4，6-三硝基苯磺酸（TNBS）诱导的结肠炎，这可能是通过其抑制IL-17介导的信号传导途径。NDR 1在溃疡性结肠炎（UC）患者的结肠中表达增加。总之，这些发现表明NDR 1参与了自身免疫性疾病的发展。
Interleukin 17 (IL-17) is an important inducer of tissue inflammation and is involved in numerous autoimmune diseases. However, how its signal transduction is regulated is not well understood. Here, we report that nuclear Dbf2-related kinase 1 (NDR1) functions as a positive regulator of IL-17 signal transduction and IL-17induced inflammation. NDR1 deficiency or knockdown inhibits the IL-17-induced phosphorylation of p38, ERK1/2, and p65 and the expression of chemokines and cytokines, whereas the overexpression of NDR1 promotes IL-17-induced signaling independent of its kinase activity. Mechanistically, NDR1 interacts with TRAF3 and prevents its binding to IL-17R, which promotes the formation of an IL-17R-Act1-TRAF6 complex and downstream signaling. Consistent with this, IL-17-induced inflammation is significantly reduced in NDR1-deficient mice, and NDR1 deficiency significantly protects mice from MOG-induced experimental autoimmune encephalomyelitis (EAE) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis likely by its inhibition of IL-17-mediated signaling pathway. NDR1 expression is increased in the colons of ulcerative colitis (UC) patients. Taken together, these findings suggest that NDR1 is involved in the development of autoimmune diseases.