Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation
Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation
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DOI：
10.1182/blood-2007-08-108316
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Locati, Massimo
中科院分区：
文献类型：
--
作者：
Bonecchi, Raffaella;Borroni, Elena M.;Locati, Massimo
诱饵受体D6通过清除炎性趋化因子在控制炎症过程中发挥非冗余作用。但目前尚不清楚如何监管。在这里，我们表明，D6清除活动依赖于独特的贩运属性。在静息条件下，D6组成型回收通过快速渥曼青霉素（WM）敏感和较慢的布雷菲德菌素A（BFA）敏感的途径，保持低水平的表面表达，需要Rab4和Rab11的活动。与被同源配体下调的“常规”趋化因子受体相反，趋化因子参与诱导剂量依赖性BFA敏感性Rab11依赖性D6重新分布至细胞膜，并相应增加趋化因子降解速率。因此，能量昂贵的组成性D6循环通过Rab11囊泡允许通过受体重新分布到质膜的趋化因子清除活性的快速的、配体浓度依赖性的增加。D6在多种细胞环境中不受转录水平的调节，因此其清除剂性能的配体依赖性优化代表了允许D6控制炎症的快速且独特的机制。
The decoy receptor D6 plays a nonredundant role in the control of inflammatory processes through scavenging of inflammatory chemokines. However it remains unclear how it is regulated. Here we show that D6 scavenging activity relies on unique trafficking properties. Under resting conditions, D6 constitutively recycled through both a rapid wortmannin (WM)-sensitive and a slower brefeldin A (BFA)-sensitive pathway, maintaining low levels of surface expression that required both Rab4 and Rab11 activities. In contrast to "conventional" chemokine receptors that are down-regulated by cognate ligands, chemokine engagement induced a dose-dependent BFA-sensitive Rab11-dependent D6 redistribution to the cell membrane and a corresponding increase in chemokine degradation rate. Thus, the energy-expensive constitutive D6 cycling through Rab11 vesicles allows a rapid, ligand concentration-dependent increase of chemokine scavenging activity by receptor redistribution to the plasma membrane. D6 is not regulated at a transcriptional level in a variety of cellular contexts, thus ligand-dependent optimization of its scavenger performance represents a rapid and unique mechanism allowing D6 to control inflammation.