PLAR binds to the annexin A2-S100A10 complex in human podocytes.

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