Sphingolipids are essential for differentiation but not growth in Leishmania

Kai Zhang, Melissa Showalter, Javier Revollo, Fong Fu Hsu, John Turk, Stephen M. Beverley

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Sphingolipids (SLs) play critical roles in eukaryotic cells in the formation of lipid rafts, membrane trafficking, and signal transduction. Here we created a SL null mutant in the protozoan parasite Leishmania major through targeted deletion of the key de novo biosynthetic enzyme serine palmitoyltransferase subunit 2 (SPT2). Although SLs are typically essential, spt2- Leishmania were viable, yet were completely deficient in de novo sphingolipid synthesis, and lacked inositol phosphorylceramides and other SLs. Remarkably, spt2- parasites maintained 'lipid rafts' as defined by Triton X-100 detergent resistant membrane formation. Upon entry to stationary phase spt2- failed to differentiate to infective metacyclic parasites and died instead. Death occurred not by apoptosis or changes in metacyclic gene expression, but from catastrophic problems leading to accumulation of small vesicles characteristic of the multivesicular body/multivesicular tubule network. Stage specificity may reflect changes in membrane structure as well as elevated demands in vesicular trafficking required for parasite remodeling during differentiation. We suggest that SL-deficient Leishmania provide a useful biological setting for tests of essential SL enzymes in other organisms where SL perturbation is lethal.

Original languageEnglish
Pages (from-to)6016-6026
Number of pages11
JournalEMBO Journal
Volume22
Issue number22
DOIs
StatePublished - Nov 17 2003

Keywords

  • Gp63-major surface protease-leishmanolysin
  • Lipophosphoglycan
  • Sphingoid base synthesis
  • Trpanosomatid parasite
  • Virulence

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    Zhang, K., Showalter, M., Revollo, J., Hsu, F. F., Turk, J., & Beverley, S. M. (2003). Sphingolipids are essential for differentiation but not growth in Leishmania. EMBO Journal, 22(22), 6016-6026. https://doi.org/10.1093/emboj/cdg584