14-3-3 Proteins regulate K_2P5.1 surface expression on T lymphocytes

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• 作者：Juncal Ferná ; ndez-Orth ; Petra Ehling ; Tobias Ruck ; Susann Pankratz ; Majella-Sophie Hofmann ; Peter Landgraf ; Daniela C. Dieterich ; Karl-Heinz Smalla ; Thilo Kä ; hne ; Guiscard Seebohm ; Thomas Budde ; Heinz Wiendl ; Stefan Bittner and Sven G. Meuth
• 刊名：Traffic
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：18
• 期：1
• 页码：29-43
• 全文大小：6636K
• ISSN：1600-0854

文摘

K_2P5.1 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 K_2P5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K_2P5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K_2P5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14-3-3 proteins as novel binding partners of K_2P5.1 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 K_2P5.1 and 14-3-3. The mutant K_2P5.1/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 K_2P5.1 and plays an important role in channel trafficking.