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    Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells.

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    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.
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    Publication Date
    2018-12-20
    Submitted date
    2018-03-26
    
    Metadata
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    Abstract
    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
    Haematologica
    URI
    http://hdl.handle.net/10034/621726
    DOI
    10.3324/haematol.2018.194241
    Type
    article
    Description
    From PubMed via Jisc Publications Router.
    History: received 2018-03-26, accepted 2018-12-19
    Publication status: aheadofprint
    ae974a485f413a2113503eed53cd6c53
    10.3324/haematol.2018.194241
    Scopus Count
    Collections
    Biological Sciences

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