Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages
Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages
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DOI：
10.4049/jimmunol.176.1.380
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Matsuda, T
中科院分区：
文献类型：
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作者：
Sekine, Y;Yumioka, T;Matsuda, T
信号转导衔接蛋白-2（STAP-2）是一种新近发现的衔接蛋白，其C端含有pleckstrin和Src同源2样结构域以及YXXQ基序。我们前期的研究已经证明STAP-2与STAT 3和STAT 5结合，并调节它们的信号通路。在本研究中，STAP-2被发现在巨噬细胞中正调节LPS/TLR 4介导的信号。STAP-2的破坏导致LPS/TLR 4诱导的细胞因子产生和NF-κ β活化受损。相反，STAP-2的过表达增强了这些LPS/TLR 4诱导的生物活性。STAP-2，特别是其Src同源2样结构域，结合MyD 88和IicB激酶（IKK）-α β，但不结合TNFR相关因子6或IL-1 R相关激酶1，并形成由MyD 88-STAP-2-IKK-α β组成的功能复合物。这些相互作用增强了MyD 88和/或IKK-α β依赖性信号，导致NF-κ β活性增强。这些结果表明，STAP-2可能构成了替代LPS/TLR 4途径的NF-κ β活化，而不是TNFR相关因子6-IL-IR相关激酶1途径。
Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-kappa beta activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and licB kinase (IKK)-alpha beta, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-alpha beta. These interactions augmented MyD88- and/or IKK-alpha beta-dependent signals, leading to enhancement of the NF-kappa beta activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-kappa beta activation instead of the TNFR-associated factor 6-IL-IRassociated kinase 1 pathway.