Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells.
Authors
Noy, Peter J.Gavin, Rebecca L.
Colombo, Dario
Haining, Elizabeth J.
Reyat, Jasmeet S.
Payne, Holly
Thielmann, Ina
Lokman, Adam B.
Neag, Georgiana
Yang, Jing
Lloyd, Tammy
Harrison, Neale
Heath, Victoria L.
Gardiner, Chris
Whitworth, Katharine M.
Robinson, Joseph
Koo, Chek Z.
Di Maio, Alessandro
Harrison, Paul
Lee, Steven P.
Michelangeli, Francesco
Kalia, Neena
Rainger, G. Ed.
Nieswandt, Bernhard
Brill, Alexander
Watson, Steve P.
Tomlinson, Michael G.
Affiliation
University of Birmingham; University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine; University College London; University Hospitals Birmingham National Health Service (NHS) Foundation Trust; University of Chester; Sechenov First Moscow State Medical UniversityPublication Date
2018-12-20
Metadata
Show full item recordAbstract
Ca entry via Orai1 store-operated Ca channels in the plasma membrane is critical to cell function, and Orai1 loss causes severe immunodeficiency and developmental defects. The tetraspanins are a superfamily of transmembrane proteins that interact with specific partner proteins and regulate their trafficking and clustering. The aim of this study was to functionally characterize tetraspanin Tspan18. We show that Tspan18 is expressed by endothelial cells at several-fold higher levels than most other cell types analyzed. Tspan18-knockdown primary human umbilical vein endothelial cells have 55-70% decreased Ca mobilization upon stimulation with the inflammatory mediators thrombin or histamine, similar to Orai1-knockdown. Tspan18 interacts with Orai1, and Orai1 cell surface localization is reduced by 70% in Tspan18-knockdown endothelial cells. Tspan18 over-expression in lymphocyte model cell lines induces 20-fold activation of Ca -responsive NFAT signaling, in an Orai1-dependent manner. Tspan18-knockout mice are viable. They lose on average 6-fold more blood in a tail-bleed assay. This is due to Tspan18 deficiency in non-hematopoietic cells, as assessed using chimeric mice. Tspan18-knockout mice have 60% reduced thrombus size in a deep vein thrombosis model, and 50% reduced platelet deposition in the microcirculation following myocardial ischemia-reperfusion injury. Histamine- or thrombin-induced von Willebrand factor release from endothelial cells is reduced by 90% following Tspan18-knockdown, and histamine-induced increase of plasma von Willebrand factor is reduced by 45% in Tspan18-knockout mice. These findings identify Tspan18 as a novel regulator of endothelial cell Orai1/Ca signaling and von Willebrand factor release in response to inflammatory stimuli. [Abstract copyright: Copyright © 2018, Ferrata Storti Foundation.]Citation
Noy, P. J., Gavin, R. L., Colombo, D., Haining, E. J., Reyat, J. S., Payne, H., Thielmann, I., Lokman, A. B., Neag, G., Yang, J., Lloyd, T., Harrison, N., Heath, V. L., Gardiner, C., Whitworth, K. M., Robinson, J., Koo, C. Z., Di Maio, A., Harrison, P., ... Tomlinson, M. G. (2019). Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells. Haematologica, 104(9). https://doi.org/10.3324/haematol.2018.194241Journal
HaematologicaAdditional Links
https://haematologica.org/article/view/9055Type
articleISSN
0390-6078ae974a485f413a2113503eed53cd6c53
10.3324/haematol.2018.194241