TRAF6 is a critical signal transducer in IL-33 signaling pathway
TRAF6 is a critical signal transducer in IL-33 signaling pathway
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DOI：
10.1016/j.cellsig.2008.05.013
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发表时间：
2008-09-01
影响因子：
4.8
通讯作者：
Kasahara, Tadashi
中科院分区：
文献类型：
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作者：
Funakoshi-Tago, Megumi;Tago, Kenji;Kasahara, Tadashi
IL-33通过IL-1受体相关蛋白ST 2L的信号传导诱导Th 2应答。然而，由ST 2L激活的信号转导途径尚未被表征。在此，我们发现在TNF受体相关因子6（TRAF 6）缺陷的MEFs中，IL-33诱导的单核细胞趋化蛋白（MCP）-1，MCP-3和IL-6的表达被显著抑制。IL-33可迅速诱导ST 2L复合物的形成，而TRAF 6的缺乏则可抑制IRAK向ST 2L的募集。因此，在TRAF 6缺陷的MEFs中，由IL-33诱导的p38、JNK和核因子-κ B（NF-κ B）活化被完全抑制。另一方面，观察到IL-33诱导的ERK活化，而不管TRAF 6的存在。TRAF 6的引入恢复了TRAM缺陷型MEFs中p38、JNK和NF-κ B的有效活化，导致MCP-1、MCP-3和IL-6表达的诱导。此外，IL-33增强了TRAM的自泛素化，并且其泛素连接酶活性缺陷的TRAF 6突变体（C70 A）的重建未能恢复IL-33诱导的p38、JNK和NF-κ B活化。因此，这些数据表明TRAF 6通过其泛素连接酶活性在IL-33信号传导途径中起关键作用。(C)2008年爱思唯尔公司All rights reserved.
IL-33 has been shown to induce Th2 responses by signaling through the IL-1 receptor-related protein, ST2L However, the signal transduction pathways activated by the ST2L have not been characterized. Here, we found that IL-33-induced monocyte chemoattractant protein (MCP)-1, MCP-3 and IL-6 expression was significantly inhibited in TNF receptor-associated Factor 6 (TRAF6)-deficient MEFs. IL-33 rapidly induced the formation of ST2L complex containing IL-1 receptor-associated kinase (IRAK), however, lack of TRAF6 abolished the recruitment of IRAK to ST2L. Consequently, p38,JNK and Nuclear factor-kappa B (NF-kappa B) activation induced by IL-33 was completely inhibited in TRAF6-deficient MEFs. On the other hand, IL-33-induced ERK activation was observed regardless of the presence of TRAF6. The introduction of TRAF6 restored the efficient activation of p38, JNK and NF-kappa B in TRAM deficient MEFs, resulting in the induction of MCP-1, MCP-3 and IL-6 expression. Moreover, IL-33 augmented autoubiquitination of TRAM and the reconstitution of TRAF6 mutant (C70A) that is defective in its ubiquitin ligase activity failed to restore IL-33-induced p38, JNK and NF-kappa B activation. Thus, these data demonstrate that TRAF6 plays a pivotal role in IL-33 signaling pathway through its ubiquitin ligase activity. (C) 2008 Elsevier Inc. All rights reserved.