Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane
Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane
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Ras 相关蛋白 Rab10 通过促进 TLR4 补充到质膜上来促进 TLR4 信号传导
DOI：
10.1073/pnas.1009428107
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发表时间：
2010-08-03
影响因子：
11.1
通讯作者：
Lu, Linrong
中科院分区：
文献类型：
--
作者：
Wang, Di;Lou, Jun;Lu, Linrong
Toll样受体（TLR）4受体复合物，TLR 4/MD-2，在针对脂多糖的炎症反应中起重要作用，脂多糖是革兰氏阴性菌中普遍存在的膜组分。TLR 4的配体识别启动多种细胞内信号传导途径，导致促炎介质和I型IFN的产生。配体相互作用还导致表面受体复合物内化到溶酶体中，导致TLR 4降解和LPS应答终止。然而，TLR 4受体复合物的表面水平通过从细胞内隔室如高尔基体和内体持续补充TLR 4来维持。在这里，我们表明，从高尔基体到质膜的TLR 4的连续补充是由小GTTRab 10调节的，这是LPS刺激后最佳巨噬细胞活化所必需的。Rab 10的表达可被LPS诱导。Rab 10功能的阻断导致LPS刺激后膜TLR 4表达减少和炎性细胞因子和干扰素的产生减少。这些发现表明Rab 10表达提供了一种通过调节TLR 4向质膜上的运输速率来改善TLR 4信号传导的机制。此外，我们发现，改变Rab 10在巨噬细胞中的表达影响疾病的严重程度在体内模型的LPS诱导的急性肺损伤，这表明Rab 10作为一个可能的治疗目标，为人类急性呼吸窘迫综合征（ARDS）。
The Toll-like receptor (TLR)4 receptor complex, TLR4/MD-2, plays an important role in the inflammatory response against lipopolysaccharide, a ubiquitous membrane component in Gram-negative bacteria. Ligand recognition by TLR4 initiates multiple intracellular signaling pathways, leading to production of proinflammatory mediators and type I IFN. Ligand interaction also leads to internalization of the surface receptor complex into lysosomes, leading to the degradation of TLR4 and the termination of LPS response. However, surface level of TLR4 receptor complex is maintained via continuous replenishment of TLR4 from intracellular compartments like Golgi and endosomes. Here we show that continuous replenishment of TLR4 from Golgi to plasma membrane is regulated by the small GTPase Rab10, which is essential for optimal macrophage activation following LPS stimulation. Expression of Rab10 is inducible by LPS. Blockade of Rab10 function leads to decreased membrane TLR4 expression and diminished production of inflammatory cytokines and interferons upon LPS stimulation. These findings suggest that Rab10 expression provides a mechanism to refine TLR4 signaling by regulating the trafficking rate of TLR4 onto the plasma membrane. In addition, we show that altered Rab10 expression in macrophages influences disease severity in an in vivo model of LPS-induced acute lung injury, suggesting Rab10 as a possible therapeutic target for human acute respiratory distress syndrome (ARDS).