Disruption of Kv1.3 Channel Forward Vesicular Trafficking by Hypoxia in Human T Lymphocytes
Disruption of Kv1.3 Channel Forward Vesicular Trafficking by Hypoxia in Human T Lymphocytes
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DOI：
10.1074/jbc.m111.274209
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发表时间：
2012-01-13
影响因子：
4.8
通讯作者：
Conforti, Laura
中科院分区：
文献类型：
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作者：
Chimote, Ameet A.;Kuras, Zerrin;Conforti, Laura
实体瘤中的缺氧通过下调T淋巴细胞中的Kv1.3通道和相关的T细胞功能抑制而导致免疫监视降低。然而，负责Kv1.3下调的机制尚不清楚。我们假设慢性缺氧通过改变膜运输减少Kv1.3表面表达。慢性缺氧降低Jurkat T细胞Kv1.3表面表达和电流密度。抑制蛋白质合成或降解和内吞作用并不能阻止这种作用。相反，阻断网格蛋白包被的囊泡的形成和正向运输防止了缺氧时Kv1.3表面表达的降低。共聚焦显微镜显示，增加保留的Kv1.3在trans-Golgi在缺氧。衔接蛋白-1（AP 1）的表达，负责网格蛋白包被的囊泡形成在trans-Golgi，选择性下调缺氧。此外，AP 1下调增加了Kv1.3在跨高尔基体中的保留并减少了Kv1.3电流。我们的研究结果表明，缺氧破坏AP 1/网格蛋白介导的正向运输Kv1.3从trans-Golgi质膜，从而有助于降低Kv1.3在T淋巴细胞表面的表达。
Hypoxia in solid tumors contributes to decreased immunosurveillance via down-regulation of Kv1.3 channels in T lymphocytes and associated T cell function inhibition. However, the mechanisms responsible for Kv1.3 down-regulation are not understood. We hypothesized that chronic hypoxia reduces Kv1.3 surface expression via alterations in membrane trafficking. Chronic hypoxia decreased Kv1.3 surface expression and current density in Jurkat T cells. Inhibition of either protein synthesis or degradation and endocytosis did not prevent this effect. Instead, blockade of clathrin-coated vesicle formation and forward trafficking prevented the Kv1.3 surface expression decrease in hypoxia. Confocal microscopy revealed an increased retention of Kv1.3 in the trans-Golgi during hypoxia. Expression of adaptor protein-1 (AP1), responsible for clathrin-coated vesicle formation at the trans-Golgi, was selectively down-regulated by hypoxia. Furthermore, AP1 down-regulation increased Kv1.3 retention in the trans-Golgi and reduced Kv1.3 currents. Our results indicate that hypoxia disrupts AP1/clathrin-mediated forward trafficking of Kv1.3 from the trans-Golgi to the plasma membrane thus contributing to decreased Kv1.3 surface expression in T lymphocytes.