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Disruption of kv1.3 channel forward vesicular trafficking by hypoxia in human T lymphocytes
Ameet A Chimote1, Zerrin Kuras, Laura Conforti
1Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Abstract:
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.
Insights
Hypoxia in tumors reduces T cell function by decreasing Kv1.3 channels. This study reveals hypoxia disrupts Kv1.3 trafficking from the Golgi, impairing T cell immunosurveillance.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Hypoxia in solid tumors impairs T cell immunosurveillance by down-regulating Kv1.3 channels.
- The precise mechanisms behind Kv1.3 channel down-regulation in T cells under hypoxic conditions remain unclear.
Purpose of the Study:
- To investigate the role of membrane trafficking in hypoxia-induced down-regulation of Kv1.3 channels in T lymphocytes.
- To elucidate the molecular mechanisms by which chronic hypoxia affects Kv1.3 surface expression and function.
Main Methods:
- Utilized Jurkat T cells subjected to chronic hypoxia.
- Assessed Kv1.3 surface expression and current density using electrophysiology and confocal microscopy.
- Investigated the involvement of protein synthesis, degradation, endocytosis, and clathrin-coated vesicle trafficking.
- Examined the expression and function of adaptor protein-1 (AP1) in the trans-Golgi network.
Main Results:
- Chronic hypoxia significantly decreased Kv1.3 surface expression and current density in T cells.
- Blocking clathrin-coated vesicle formation and forward trafficking prevented Kv1.3 down-regulation.
- Hypoxia led to increased retention of Kv1.3 in the trans-Golgi and down-regulated AP1 expression.
- Down-regulation of AP1 exacerbated Kv1.3 retention and reduced Kv1.3 currents.
Conclusions:
- Hypoxia disrupts the AP1/clathrin-mediated forward trafficking of Kv1.3 channels from the trans-Golgi to the plasma membrane.
- This trafficking disruption contributes to decreased Kv1.3 surface expression in T lymphocytes, potentially impairing T cell function and immunosurveillance in the tumor microenvironment.
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There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...