TY - JOUR
T1 - Phospholipase A2IVα regulates phagocytosis independent of its enzymatic activity
AU - Zizza, Pasquale
AU - Iurisci, Cristiano
AU - Bonazzi, Matteo
AU - Cossart, Pascale
AU - Leslie, Christina C.
AU - Corda, Daniela
AU - Mariggio, Stefania
PY - 2012/5/11
Y1 - 2012/5/11
N2 - Group IVα phospholipase A2 (PLA2IVα) is a lipolytic enzyme that catalyzes the hydrolysis of membrane phospholipids to generate precursors of potent inflammatory lipid mediators. Here, the role of PLA2IVα in Fc receptor (FcR)-mediated phagocytosis was investigated, demonstrating that PLA2IVα 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 PLA2IVα by pyrrophenone reduces particle internalization by up to 50%. In parallel, fibroblasts from PLA 2IVα knock-out mice overexpressing FcγRIIA and able to internalize IgG-opsonized beads show 50% lower phagocytosis, compared with wild-type cells, and transfection of PLA2IVα fully recovers this impaired function. Interestingly, transfection of the catalytically inactive deleted PLA2IVαmutant (PLA2IVα(1-525) ) and point mutant (PLA2IVα- S228C) also promotes recovery of this impaired function. Finally, transfection of the PLA2IVα C2 domain (which is directly involved in PLA2IVα membrane binding), but not of PLA2IVα-D43N (which cannot bind to membranes), rescues FcR-mediated phagocytosis. These data unveil a new mechanism of action for PLA2IVα, which demonstrates that the membrane binding, and not the enzymatic activity, is required for PLA 2IVα modulation of FcR-mediated phagocytosis.
AB - Group IVα phospholipase A2 (PLA2IVα) is a lipolytic enzyme that catalyzes the hydrolysis of membrane phospholipids to generate precursors of potent inflammatory lipid mediators. Here, the role of PLA2IVα in Fc receptor (FcR)-mediated phagocytosis was investigated, demonstrating that PLA2IVα 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 PLA2IVα by pyrrophenone reduces particle internalization by up to 50%. In parallel, fibroblasts from PLA 2IVα knock-out mice overexpressing FcγRIIA and able to internalize IgG-opsonized beads show 50% lower phagocytosis, compared with wild-type cells, and transfection of PLA2IVα fully recovers this impaired function. Interestingly, transfection of the catalytically inactive deleted PLA2IVαmutant (PLA2IVα(1-525) ) and point mutant (PLA2IVα- S228C) also promotes recovery of this impaired function. Finally, transfection of the PLA2IVα C2 domain (which is directly involved in PLA2IVα membrane binding), but not of PLA2IVα-D43N (which cannot bind to membranes), rescues FcR-mediated phagocytosis. These data unveil a new mechanism of action for PLA2IVα, which demonstrates that the membrane binding, and not the enzymatic activity, is required for PLA 2IVα modulation of FcR-mediated phagocytosis.
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U2 - 10.1074/jbc.M111.309419
DO - 10.1074/jbc.M111.309419
M3 - Article
C2 - 22393044
AN - SCOPUS:84860850907
VL - 287
SP - 16849
EP - 16859
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 20
ER -