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首页> 外文期刊>The journal of immunology >Cytoplasmic Linker Protein CLIP170 Negatively Regulates TLR4 Signaling by Targeting the TLR Adaptor Protein TIRAP
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Cytoplasmic Linker Protein CLIP170 Negatively Regulates TLR4 Signaling by Targeting the TLR Adaptor Protein TIRAP

机译：细胞质接头蛋白CLIP170通过靶向TLR衔接子蛋白TIRAP负调控TLR4信号传导

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Cytoplasmic linker protein 170 (CLIP170) is a CAP-Gly domain–containing protein that is associated with the plus end of growing microtubules and implicated in various cellular processes, including the regulation of microtubule dynamics, cell migration, and intracellular transport. Our studies revealed a previously unrecognized property and role of CLIP170. We identified CLIP170 as one of the interacting partners of Brucell a effector protein TcpB that negatively regulates TLR2 and TLR4 signaling. In this study, we demonstrate that CLIP170 interacts with the TLR2 and TLR4 adaptor protein TIRAP. Furthermore, our studies revealed that CLIP170 induces ubiquitination and subsequent degradation of TIRAP to negatively regulate TLR4-mediated proinflammatory responses. Overexpression of CLIP170 in mouse macrophages suppressed the LPS-induced expression of IL-6 and TNF-α whereas silencing of endogenous CLIP170 potentiated the levels of proinflammatory cytokines. In vivo silencing of CLIP170 in C57BL/6 mice by CLIP170-specific small interfering RNA enhanced LPS-induced IL-6 and TNF-α expression. Furthermore, we found that LPS modulates the expression of CLIP170 in mouse macrophages. Overall, our experimental data suggest that CLIP170 serves as an intrinsic negative regulator of TLR4 signaling that targets TIRAP.
机译：细胞质接头蛋白170（CLIP170）是一种含有CAP-Gly结构域的蛋白，与生长中的微管的正端相关，并涉及各种细胞过程，包括微管动力学，细胞迁移和细胞内运输的调控。我们的研究揭示了CLIP170以前无法识别的特性和作用。我们将CLIP170确定为Brucell效应蛋白TcpB的相互作用伴侣之一，该蛋白负面调节TLR2和TLR4信号传导。在这项研究中，我们证明CLIP170与TLR2和TLR4衔接蛋白TIRAP相互作用。此外，我们的研究表明，CLIP170诱导泛素化和随后的TIRAP降解，从而负面调节TLR4介导的促炎反应。小鼠巨噬细胞中CLIP170的过表达抑制了LPS诱导的IL-6和TNF-α的表达，而内源性CLIP170的沉默增强了促炎细胞因子的水平。 CLIP170特异性小干扰RNA对C57BL / 6小鼠体内CLIP170的沉默增强了LPS诱导的IL-6和TNF-α表达。此外，我们发现LPS调节小鼠巨噬细胞中CLIP170的表达。总体而言，我们的实验数据表明，CLIP170充当靶向TIRAP的TLR4信号的内在负调节剂。

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