Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)

Goretzko, J.; Heitzig, N.; Thomas, K.; Krogsaeter, E. K.; Nass, J.; Linard Matos, A. L.; Wegner, T.; Schloer, S.; Gerke, V.; Rossaint, J.; Glorius, F.; Bracher, F.; Grimm, C. M.; Rescher, U.

doi:10.1101/2021.09.28.462104

bioRxiv · 10.1101/2021.09.28.462104

Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)

Goretzko, J.·Heitzig, N.·Thomas, K.·Krogsaeter, E. K.·Nass, J.·Linard Matos, A. L.·Wegner, T.·Schloer, S.·Gerke, V.·Rossaint, J.·Glorius, F.·Bracher, F.·Grimm, C. M.·Rescher, U.

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Abstract

In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leukocyte receptor P-selectin together with the stabilizing co-factor CD63. We found that diminished expression of the endolysosomal non-selective cation channel TPC2 or inhibition of TPC2-mediated Ca2+-release via trans-Ned 19 led to reduced endolysosomal Ca2+ efflux, and blocked transfer of CD63 from late endosomes/lysosomes (LEL) to WPB, and a concomitant loss of P-selectin on the endothelial cell surface. Accordingly, P-selectin-mediated leukocyte recruitment to trans-Ned 19-treated HUVEC under flow was significantly reduced without disturbing VWF exocytosis. Our findings establish the endolysosome-related TPC2 Ca2+ channel as a key element in the maintenance of proper endothelial functions and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

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Goretzko, J., Heitzig, N., Thomas, K., Krogsaeter, E. K., Nass, J., Linard Matos, A. L., Wegner, T., Schloer, S., Gerke, V., Rossaint, J., Glorius, F., Bracher, F., Grimm, C. M., Rescher, U.. 2021-09-28. Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2). https://doi.org/10.1101/2021.09.28.462104

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