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Sphingolipid‐free Leishmania are defective in membrane trafficking, differentiation and infectivity
Author(s) -
Denny Paul W.,
Goulding David,
Ferguson Michael A. J.,
Smith Deborah F.
Publication year - 2004
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2003.03975.x
Subject(s) - sphingolipid , biology , microbiology and biotechnology , ceramide , leishmania , sphingomyelin , infectivity , leishmania major , lipid raft , biochemistry , signal transduction , genetics , membrane , apoptosis , parasite hosting , virus , world wide web , computer science
Summary Sphingolipids are structural components of the eukaryotic plasma membrane that are involved, together with cholesterol, in the formation of lipid microdomains (rafts). Additionally, sphingolipid metabolites have been shown to modulate a wide variety of cellular events, including differentiation and apoptosis. To investigate the role of de novo sphingolipid biosynthesis in Leishmania , we have focused on serine palmitoyltransferase (SPT), which catalyses the first, rate‐limiting step in the synthetic pathway. Genetic ablation of one SPT subunit, Lm LCB2, yields viable null parasites that can no longer synthesize ceramide and sphingolipids de novo . Unexpectedly, Lm LCB2 expression (and sphingolipid biosynthesis) is stage regulated in Leishmania , being undetectable in intramacrophage parasites. As expected from this observation, the Lm LCB2 null mutants maintain infectivity in vivo . However, they are compromised in their ability to form infective extracellular parasites, correlating with a defect in association of the virulence factor, leishmanolysin or GP63, with lipid rafts during exocytosis and an observed relocalization of a second virulence factor, lipophosphogycan, during differentiation. Thus, de novo sphingolipid biosynthesis is critical for membrane trafficking events in extracellular Leishmania but has at best a minor role in intracellular pathogenesis.