14‐3‐3 Proteins regulate K2P5.1 surface expression on T lymphocytes |
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| Authors: | Juncal Fernández‐Orth Petra Ehling Tobias Ruck Susann Pankratz Majella‐Sophie Hofmann Peter Landgraf Daniela C Dieterich Karl‐Heinz Smalla Thilo Kähne Guiscard Seebohm Thomas Budde Heinz Wiendl Stefan Bittner Sven G Meuth |
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| Institution: | 1. Department of Neurology, Westf?lische Wilhelms‐Universit?t, Münster, Germany;2. Neural Plasticity and Communication, Institute for Pharmacology and Toxicology, Otto von‐Guericke‐University, Magdeburg, Germany;3. Center for Behavioral Brain Sciences (CBBS), Otto von-Guericke-University, Magdeburg, Germany;4. Special Lab Molecular Biological Techniques, Leibniz Institute for Neurobiology, Magdeburg, Germany;5. Institute of Experimental Internal Medicine, Medical Faculty, Otto‐von‐Guericke‐University, Magdeburg, Germany;6. Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany;7. Institute for Physiology I, Westf?lische Wilhelms‐Universit?t, Münster, Germany;8. Department of Neurology, University Medical Center, Johannes Gutenberg‐University, Mainz, Germany |
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| Abstract: | K2P5.1 channels (also called TASK‐2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P5.1 channels in vitro provokes enhanced T‐cell effector functions. However, the molecular mechanisms regulating intracellular K2P5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14‐3‐3 proteins as novel binding partners of K2P5.1 channels. We show that a non‐classical 14‐3‐3 consensus motif (R‐X‐X‐pT/S‐x) at the channel's C‐terminus allows the binding between K2P5.1 and 14‐3‐3. The mutant K2P5.1/S266A diminishes the protein‐protein interaction and reduces the amplitude of membrane currents. Application of a non‐peptidic 14‐3‐3 inhibitor (BV02) significantly reduces the number of wild‐type channels in the plasma membrane, whereas the drug has no effect on the trafficking of the mutated channel. Furthermore, blocker application reduces T‐cell effector functions. Taken together, we demonstrate that 14‐3‐3 interacts with K2P5.1 and plays an important role in channel trafficking.  |
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| Keywords: | 14‐3‐3 K2P5 1 membrane trafficking multiple sclerosis T‐cells |
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