2. Academic Validation
  3. 14-3-3 Proteins regulate K2P 5.1 surface expression on T lymphocytes

14-3-3 Proteins regulate K2P 5.1 surface expression on T lymphocytes

  • Traffic. 2017 Jan;18(1):29-43. doi: 10.1111/tra.12455.
Juncal Fernández-Orth 1,  Petra Ehling 1,  Tobias Ruck 1,  Susann Pankratz 1,  Majella-Sophie Hofmann 1,  Peter Landgraf 2,  Daniela C Dieterich 2 3,  Karl-Heinz Smalla 4,  Thilo Kähne 5,  Guiscard Seebohm 6,  Thomas Budde 7,  Heinz Wiendl 1,  Stefan Bittner 8,  Sven G Meuth 1
Affiliations

Affiliations

  • 1 Department of Neurology, Westfälische Wilhelms-Universität, 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, Westfälische Wilhelms-Universität, Münster, Germany.
  • 8 Department of Neurology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
PMID: 27743426 DOI: 10.1111/tra.12455
Abstract

K2P 5.1 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 K2P 5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P 5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P 5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14-3-3 proteins as novel binding partners of K2P 5.1 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 K2P 5.1 and 14-3-3. The mutant K2P 5.1/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 K2P 5.1 and plays an important role in channel trafficking.

Keywords

14-3-3; K2P5.1; T-cells; membrane trafficking; multiple sclerosis.

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