Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University Medical School, Lisbon, Portugal.
Blood. 2010 Apr 22;115(16):3269-77. doi: 10.1182/blood-2009-10-246876. Epub 2010 Feb 26.
Interleukin-7 (IL-7) is an essential cytokine for T-cell development and homeostasis. It is well established that IL-7 promotes the transcriptional down-regulation of IL7RA, leading to decreased IL-7Ralpha surface expression. However, it is currently unknown whether IL-7 regulates the intracellular trafficking and early turnover of its receptor on ligand binding. Here, we show that, in steady-state T cells, IL-7Ralpha is slowly internalized and degraded while a significant fraction recycles back to the surface. On IL-7 stimulation, there is rapid IL-7Ralpha endocytosis via clathrin-coated pits, decreased receptor recycling, and accelerated lysosome and proteasome-dependent degradation. In accordance, the half-life of IL-7Ralpha decreases from 24 hours to approximately 3 hours after IL-7 treatment. Interestingly, we further demonstrate that clathrin-dependent endocytosis is necessary for efficient IL-7 signal transduction. In turn, pretreatment of T cells with JAK3 or pan-JAK inhibitors suggests that IL-7Ralpha degradation depends on the activation of the IL-7 signaling effector JAK3. Overall, our findings indicate that IL-7 triggers rapid IL-7Ralpha endocytosis, which is required for IL-7-mediated signaling and subsequent receptor degradation.
白细胞介素-7（IL-7）是 T 细胞发育和稳态所必需的细胞因子。已经证实，IL-7 促进 IL7RA 的转录下调，导致 IL-7Ralpha 表面表达减少。然而，目前尚不清楚 IL-7 是否调节其配体结合时受体的细胞内运输和早期周转。在这里，我们表明，在稳态 T 细胞中，IL-7Ralpha 缓慢内化并降解，而相当一部分则重新循环到表面。在 IL-7 刺激下，通过网格蛋白包被的陷窝快速进行 IL-7Ralpha 内吞作用，减少受体的回收，并加速溶酶体和蛋白酶体依赖性降解。相应地，IL-7 处理后，IL-7Ralpha 的半衰期从 24 小时缩短至约 3 小时。有趣的是，我们进一步证明网格蛋白依赖性内吞作用对于有效的 IL-7 信号转导是必要的。反过来，用 JAK3 或泛 JAK 抑制剂预处理 T 细胞表明，IL-7Ralpha 的降解依赖于 IL-7 信号转导效应子 JAK3 的激活。总体而言，我们的发现表明，IL-7 触发快速的 IL-7Ralpha 内吞作用，这对于 IL-7 介导的信号转导和随后的受体降解是必需的。
