PLA(2)R 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.