Disruption of Kv1.3 Channel Forward Vesicular Trafficking by Hypoxia in Human T Lymphocytes

• Published in: The Journal of biological chemistry Vol. 287; no. 3; pp. 2055 - 2067
• Main Authors: Chimote, Ameet A., Kuras, Zerrin, Conforti, Laura
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-01-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Biology; Cell Hypoxia - physiology; Clathrin; Clathrin-Coated Vesicles - genetics; Clathrin-Coated Vesicles - metabolism; Dynamin; Gene Expression Regulation - physiology; Humans; Hypoxia; Ion Channels; Jurkat Cells; Kv1.3; Kv1.3 Potassium Channel - biosynthesis; Kv1.3 Potassium Channel - genetics; Membrane Trafficking; Potassium Channels; T Cell; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Trans-Golgi; trans-Golgi Network - genetics; trans-Golgi Network - metabolism; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Membrane Trafficking; Potassium Channels; Trans-Golgi; Clathrin; Ion Channels; T Cell; Dynamin; Hypoxia; Kv1.3
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.274209

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.
Background: Chronic hypoxia decreases Kv1.3 channel surface expression in T lymphocytes.
Results: Hypoxia blocks clathrin-mediated forward trafficking of Kv1.3 in the trans-Golgi. Hypoxia down-regulates adaptor protein 1 (AP1), required for formation of clathrin-coated vesicles.
Conclusion: Hypoxia disrupts AP1/clathrin mediated forward trafficking of Kv1.3 from the trans-Golgi to the plasma membrane.
Significance: Mechanism for reduced immune surveillance by T cells in hypoxic tumors.