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

Phospholipase A₂ receptor (PLA₂R) is a member of the mannose receptor family found in podocytes in human kidney. PLA₂R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA₂R autoantibodies which bind to the podocyte. However the function of PLA₂R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA₂R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA₂R. We confirmed that PLA₂R binds to annexinA2-S100A10 (A2t) complex with specific high affinity to the S100A10 component. The binding occured within the PLA₂R NC3 fragment and was increased in acidic pH. Furthermore Ca²⁺ promoted the association of the PLA₂R-A2t complex with phospholipid membranes in vitro. Within the podocyte, all three proteins were enriched in the plasma membrane and organelle membrane compartments. PLA₂R co-localised with S100A10 at the cell surface and in extracellular vesicles. This novel interaction between PLA₂R and the A2t complex offers insights into the role of PLA₂R in podocytes and how autoantibodies might disrupt PLA₂R function. The ability of podocytes to secrete vesicles containing PLA₂R provides a route for engagement of PLA₂R with the immune system.