Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63

Abstract

To enable leukocyte adhesion to activated endothelium, the leukocyte receptor P-selectin is released from Weibel-Palade bodies (WPB) to the endothelial cell surface where it is stabilized by CD63. Here we report that loss of annexin A8 (anxA8) in human umbilical vein endothelial cells (HUVEC) strongly decreases cell surface presentation of CD63 and P-selectin, with a concomitant reduction in leukocyte rolling and adhesion. We confirm the compromised leukocyte adhesiveness in inflammatory-activated endothelial venules of anxA8-deficient mice. We find that WPB of anxA8-deficient HUVEC contain less CD63, and that this is caused by improper transport of CD63 from late multivesicular endosomes to WPB, with CD63 being retained in intraluminal vesicles. Consequently, reduced CD63 cell surface levels are seen following WPB exocytosis, resulting in enhanced P-selectin re-internalization. Our data support a model in which anxA8 affects leukocyte recruitment to activated endothelial cells by supplying WPB with sufficient amounts of the P-selectin regulator CD63.

Regulation of retinal pigment epithelial cell phenotype by Annexin A8

“…AnxA8 was first identified as vascular anticoagulant-β in the human placenta, where it was described to inhibit blood coagulation and phospholipase A 2 26 . AnxA8 has been linked with endosome formation in Hela cells 27 , and it plays a role in leukocyte recruitment through exposing cell surface markers on endothelial cells such as CD63 and P-selectin 28 . We show here that suppression of AnxA8 phenocopies the effects of FR, and is both necessary and sufficient to induce neuronal transdifferentiation of RPE cells.…”

Quantitative Characterization of E-selectin Interaction with Native CD44 and P-selectin Glycoprotein Ligand-1 (PSGL-1) Using a Real Time Immunoprecipitation-based Binding Assay

“…Our results, in conjunction with previous work, underscore the importance of particular cell surface presentations of selectins or their ligands during leukocyte rolling on vascular surfaces under flow. Recent studies elaborated on the existence and significance of P-and E-selectin clustering and on the regulation of P-selectin clustering in leukocyte recruitment (23,24,(45)(46)(47). These studies so eloquently show that clustering of Pand E-selectins in clathrin-coated pits and lipid rafts of endothelial cells supports slower rolling of leukocytes by forming bond clusters with PSGL-1 and that if these structures are disrupted rolling is inhibited.…”

“…Furthermore, the dimerization/ oligomerization of P-selectin on endothelial cells is actually mediated by a tetraspanin, CD63, which is essential for the correct organization and function of P-selectin (45). Moreover, CD63 is regulated by annexinA8, a membrane-trafficking protein required for the delivery of CD63 to WeibelPalade bodies where P-selectin is stored (46). No publication to date has reported such mechanisms of regulation of E-selectin oligomerization.…”

mRNA/lncRNA expression patterns and the function of fibrinogen‐like protein 2 in Meishan pig endometrium during the preimplantation phases

“…This protein may modulate signal transduction either directly by interacting with the EGF receptor or indirectly by interacting with the EGF pathway regulators (Wos & Bandorowicz‐Pikula, ). Another study proposed a model in which ANXA8 affects leukocyte recruitment to activate endothelial cells (Poeter et al, ). FGL2 appears to be physiologically expressed and may protect against the internal danger of maternal and fetal bleeding during pregnancy and at parturition (Clark et al, ).…”