Plasminogen receptors promote lipoprotein(a) uptake by enhancing surface binding and facilitating macropinocytosis
High levels of lipoprotein(a) [Lp(a)] are associated with multiple forms of cardiovascular disease (CVD). Lp(a) consists of a low-density lipoprotein (LDL) attached to the plasminogen homologue, apolipoprotein(a) [apo(a)]. We previously discovered that the plasminogen receptor, plasminogen receptor with a C-terminal lysine (PlgRKT), promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of two other plasminogen receptors, Annexin A2 and S100 calcium binding protein A10 (S100A10) in the endocytosis of Lp(a). Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were utilised for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL, apo(a) and endocytic cargos was visualised and quantified by confocal microscopy and by western blotting. The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, Annexin A2 or S100A10. Conversely, both Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not Annexin A2 or S100A10, increased Lp(a) binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker, dextran, when overexpressed in HepG2 and HAP1 cells, and a knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K inhibitor, known to inhibit macropinocytosis on Lp(a) uptake. Results showed a concentration dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis. These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors which both enhance surface binding and stimulate macropinocytosis of Lp(a).
Meeting ID: 977 5670 4741
|Date||Tuesday, 4 October 2022|
|Time||12:00pm - 1:00pm|
Online and in-person
|Location||Biochemistry Seminar Room G.13 (BIG13) and via Zoom, Dunedin|
|Contact Name||Department of Biochemistry|