PLA2R binds to the annexin A2-S100A10 complex in human podocytes

Phospholipase A 2 receptor (PLA 2 R) is a member of the mannose receptor family found in podocytes in human kidney. PLA 2 R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA 2 R autoantibodies which bind to the podocyte. However the function of PLA 2 R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA 2 R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA 2 R. We confirmed that PLA 2 R binds to annexinA2-S100A10 (A2t) complex with specific high affinity to the S100A10 component. The binding occured within the PLA 2 R NC3 fragment and was increased in acidic pH. Furthermore Ca 2+ promoted the association of the PLA 2 R-A2t complex with phospholipid membranes in vitro . Within the podocyte, all three proteins were enriched in the plasma membrane and organelle membrane compartments. PLA 2 R co-localised with S100A10 at the cell surface and in extracellular vesicles. This novel interaction between PLA 2 R and the A2t complex offers insights into the role of PLA 2 R in podocytes and how autoantibodies might disrupt PLA 2 R function. The ability of podocytes to secrete vesicles containing PLA 2 R provides a route for engagement of PLA 2 R with the immune system.