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

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.

Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin

“…In addition, an additional phospholipid-binding domain that contains about 40 predominantly basic amino acids exists in the first cytosolic loop of mammalian PMCAs, providing the second binding site for acidic phospholipids 17 . Recently, two immunoglobulin (Ig) superfamily proteins, neuroplastin (NPTN) and basigin (BASI), were identified as previously unrecognized obligatory subunits of PMCAs and essential for the efficient control of the PMCA-mediated Ca 2+ clearance 10 , 18 , 19 . However, detailed structural information is unavailable for NPTN- or BASI-bound PMCAs and the molecular mechanism underlying the active effect of the subunits on PMCAs.…”

TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin

“…Consistent with this proposition, it has been reported recently that TRAF6 efficiently binds to and regulates the stability of PSD-95 as a necessary step for the plasticity of hippocampal mature spines (Ma et al, 2017). Alternatively, neuroplastin could also change its predilection for interaction partners in young neurons as it becomes an essential subunit for the four paralogs in mature neurons (Bhattacharya et al, 2017;Herrera-Molina et al, 2017;Korthals et al, 2017;Schmidt et al, 2017;Gong et al, 2018).…”

“…Very recently, it has been discovered that neuroplastin interacts with all four plasma membrane Ca 2+ ATPases (PMCA1-4) stabilizing the surface expression of these pumps (Bhattacharya et al, 2017;Herrera-Molina et al, 2017;Korthals et al, 2017;Schmidt et al, 2017;Gong et al, 2018). Thus, we addressed the obvious question whether TRAF6 or neuroplastin require PMCA to promote dendritic protrusion density.…”

Neuroplastin 65 modulates anxiety‐ and depression‐like behavior likely through adult hippocampal neurogenesis and central 5‐HT activity

“…More recently, Schmidt et al [11] identified Nptn as a novel subunit of native plasma membrane Ca 2+ -ATPases (PMCAs). In addition, Korthals et al [12] reported that PMCA levels were dramatically reduced and Ca 2+ levels were significantly increased in internal stores of Nptn À/À T cells. These reports suggest that Nptn may be a key regulator of intracellular Ca 2+ concentration, through which it may influence behaviors and brain function in rodents.…”