Phospholipase A2IValpha regulates phagocytosis independent of its enzymatic activity

Group IV? phospholipase A(2) (PLA(2)IV?) is a lipolytic enzyme that catalyzes the hydrolysis of membrane phospholipids to generate precursors of potent inflammatory lipid mediators. Here, the role of PLA(2)IV? in Fc receptor (FcR)-mediated phagocytosis was investigated, demonstrating that PLA(2)IV? is selectively activated upon FcR-mediated phagocytosis in macrophages and that it rapidly translocates to the site of the nascent phagosome. Moreover, pharmacological inhibition of PLA(2)IV? by pyrrophenone reduces particle internalization by up to 50%. In parallel, fibroblasts from PLA(2)IV? knock-out mice overexpressing Fc?RIIA and able to internalize IgG-opsonized beads show 50% lower phagocytosis, compared with wild-type cells, and transfection of PLA(2)IV? fully recovers this impaired function. Interestingly, transfection of the catalytically inactive deleted PLA(2)IV? mutant (PLA(2)IV?(1-525)) and point mutant (PLA(2)IV?-S228C) also promotes recovery of this impaired function. Finally, transfection of the PLA(2)IV? C2 domain (which is directly involved in PLA(2)IV? membrane binding), but not of PLA(2)IV?-D43N (which cannot bind to membranes), rescues FcR-mediated phagocytosis. These data unveil a new mechanism of action for PLA(2)IV?, which demonstrates that the membrane binding, and not the enzymatic activity, is required for PLA(2)IV? modulation of FcR-mediated phagocytosis.