Abstract
The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. The regulatory subunit KCNE4 acts as an ancillary peptide of Kv1.3, modulates K+ currents and controls channel abundance at the cell surface. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Thus, KCNE4 is crucial for Ca2+-dependent Kv1.3-related leukocyte functions. To better understand the role of KCNE4 in the regulation of the immune system, we manipulated its expression in various leukocyte cell lines. Jurkat T lymphocytes exhibit low KCNE4 levels, whereas CY15 dendritic cells, a model of professional antigen-presenting cells, robustly express KCNE4. When the cellular KCNE4 abundance was increased in T cells, the interaction between KCNE4 and Kv1.3 affected important T cell physiological features, such as channel rearrangement in the immunological synapse, cell growth, apoptosis and activation, as indicated by decreased IL-2 production. Conversely, ablation of KCNE4 in dendritic cells augmented proliferation. Furthermore, the LPS-dependent activation of CY15 cells, which induced Kv1.3 but not KCNE4, increased the Kv1.3-KCNE4 ratio and increased the expression of free Kv1.3 without KCNE4 interaction. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions.
Highlights
The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis
To visualize Kv1.3 and KCNE4 localization in immune cells, we performed Induced patching immunocytochemistry (IPI) immunocytochemistry to enhance the KCNE4 signal in T cells. This showed that Kv1.3 and KCNE4 colocalized in CY15 cells and to a lesser extent in Jurkat T cells (Fig. 1D)
Our work shows that KCNE4 controls the membrane abundance and the spatial localization of Kv1.3 channels in immune cells, such as T lymphocytes and dendritic cells
Summary
The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions. Given that KCNE4 associates with Kv1.3 in leukocytes undergoing differential regulation and tightly controls channel function in heterologous expression s ystems[16,17,18,19], we aimed to decipher the role of KCNE4 in immune cell physiology under different scenarios. We altered the expression of KCNE4 in Jurkat T lymphocytes and CY15 dendritic cells (APCs) and analyzed the functional consequences on Kv1.3-related leukocyte physiology. We found that KCNE4 fine-tunes the immunological response by modulating a number of events, such as delocalization from the IS, IL-2 production in T-cells, APC activation, proliferation and apoptosis. Our data unequivocally situate KCNE4 as a central regulator in leukocytes, indicating that KCNE4 should be considered a promising target in the development of therapeutic strategies for the treatment of Kv1.3-related immunological disorders
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