γ-Secretase Is a Functional Component of Phagosomes

Abstract γ-Secretase is a high molecular mass protein complex that catalyzes the intramembrane cleavage of its protein substrates. Two proteins involved in phagocytosis, CD44 and the low density lipoprotein receptor-related protein, are γ-secretase substrates, suggesting that this complex might regulate some aspects of phagocytosis. Our results indicate that the four components of γ-secretase, viz. presenilin, nicastrin, APH-1, and PEN-2, are present and enriched on phagosome membranes from both murine macrophages and Drosophila S2 phagocytes. The γ-secretase components form high molecular mass complexes in lipid microdomains of the phagosome membrane with the topology expected for the functional enzyme. In contrast to the majority of the phagosome proteins studied so far, which appear to associate transiently with this organelle, γ-secretase resides on newly formed phagosomes and remains associated throughout their maturation into phagolysosomes. Finally, our results indicate that interferon-γ stimulates γ-secretase-dependent cleavages on phagosomes and that γ-secretase activity may be involved in the phagocytic response of macrophages to inflammatory cytokines.