Gamma-secretase is a functional component of phagosomes.
Gamma-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 gamma-secretase substrates, suggesting that this complex might regulate some aspects of phagocytosis. Our results indicate that the four components of gamma-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 gamma-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, gamma-secretase resides on newly formed phagosomes and remains associated throughout their maturation into phagolysosomes. Finally, our results indicate that interferon-gamma stimulates gamma-secretase-dependent cleavages on phagosomes and that gamma-secretase activity may be involved in the phagocytic response of macrophages to inflammatory cytokines.
Jutras
Isabelle
I
Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Laplante
Annie
A
Boulais
Jonathan
J
Brunet
Sylvain
S
Thinakaran
Gopal
G
Desjardins
Michel
M
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism / Q000502:physiology*; D006031:Glycosylation; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D011973:Receptors, LDL; C413604:nicastrin protein; D007371:Interferon-gamma; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse