Lipidomics Suggests a New Role for Ceramide Synthase in Phagocytosis

Phagocytosis
is an evolutionarily conserved biological process where pathogens
or cellular debris are cleared by engulfing them in a membrane-enclosed
cellular compartment called the phagosome. The formation, maturation,
and subsequent degradation of a phagosome is an important immune response
essential for protection against many pathogens. Yet, the global lipid
profile of phagosomes remains unknown, especially as a function of
their maturation in immune cells. Here, we show using mass spectrometry
based quantitative lipidomics that the ceramide class of lipids, especially
very long chain ceramides, are enriched on maturing phagosomes with
a concomitant decrease in the biosynthetic precursors of ceramides.
We thus posit a new function for the enzyme ceramide synthase during
phagocytosis in mammalian macrophages. Biochemical assays, cellular
lipid feeding experiments, and pharmacological blockade of ceramide
synthase together show that this enzyme indeed controls the flux of
ceramides on maturing phagosomes. We also find similar results in
the primitive eukaryote Dictyostelium discoideum,
suggesting that ceramide enrichment may be evolutionarily conserved
and likely an indispensible step in phagosome maturation.