A complex of Neuroplastin and Plasma Membrane Ca2+ ATPase controls T cell activation

Sci Rep. 2017 Aug 21;7(1):8358. doi: 10.1038/s41598-017-08519-4.

Mark Korthals ¹ ², Kristina Langnaese ¹, Karl-Heinz Smalla ² ³, Thilo Kähne ⁴, Rodrigo Herrera-Molina ², Juliane Handschuh ², Anne-Christin Lehmann ¹, Dejan Mamula ¹, Michael Naumann ⁴, Constanze Seidenbecher ² ³, Werner Zuschratter ⁵, Kerry Tedford ¹, Eckart D Gundelfinger ² ³ ⁶ ⁷, Dirk Montag ⁸, Klaus-Dieter Fischer ⁹, Ulrich Thomas ¹⁰

Affiliations

1 Institute of Biochemistry and Cell Biology, Otto-von-Guericke-University, Medical Faculty, D-39120, Magdeburg, Germany.
2 Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, D-39118, Magdeburg, Germany.
3 Center for Behavioral Brain Sciences, D-39120, Magdeburg, Germany.
4 Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Medical Faculty, D-39120, Magdeburg, Germany.
5 Special Lab Electron and Laserscanning Microscopy, Leibniz Institute for Neurobiology, D-39118, Magdeburg, Germany.
6 Medical Faculty, Otto von Guericke University, D-39120, Magdeburg, Germany.
7 German Center for Neurodegenerative Diseases (DZNE) Site Magdeburg, D-39120, Magdeburg, Germany.
8 Neurogenetics Special Laboratory, Leibniz Institute for Neurobiology, D-39118, Magdeburg, Germany.
9 Institute of Biochemistry and Cell Biology, Otto-von-Guericke-University, Medical Faculty, D-39120, Magdeburg, Germany. klaus.fischer@med.ovgu.de.
10 Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, D-39118, Magdeburg, Germany. Ulrich.Thomas@lin-magdeburg.de.

PMID: 28827723 DOI: 10.1038/s41598-017-08519-4

Abstract

The outcome of T cell activation is determined by mechanisms that balance CA²⁺ influx and clearance. Here we report that murine CD4 T cells lacking Neuroplastin (Nptn ^-/-), an immunoglobulin superfamily protein, display elevated cytosolic CA²⁺ and impaired post-stimulation CA²⁺ clearance, along with increased nuclear levels of NFAT transcription factor and enhanced T cell receptor-induced cytokine production. On the molecular level, we identified plasma membrane CA²⁺ ATPases (PMCAs) as the main interaction partners of Neuroplastin. PMCA levels were reduced by over 70% in Nptn ^-/- T cells, suggesting an explanation for altered CA²⁺ handling. Supporting this, CA²⁺ extrusion was impaired while CA²⁺ levels in internal stores were increased. T cells heterozygous for PMCA1 mimicked the phenotype of Nptn ^-/- T cells. Consistent with sustained CA²⁺ levels, differentiation of Nptn ^-/- T helper cells was biased towards the Th1 versus Th2 subset. Our study thus establishes Neuroplastin-PMCA modules as important regulators of T cell activation.

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