Leishmania LPG3 encodes a GRP94 homolog required for phosphoglycan synthesis implicated in parasite virulence but not viability

Albert Descoteaux, Herbert A. Avila, Kai Zhang, Salvatore J. Turco, Stephen M. Beverley

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Leishmania promastigotes express an abundant cell surface glycoconjugate, lipophosphoglycan (LPG). LPG contains a polymer of the disaccharide-phosphate repeat unit Galβ1,4Manα1-PO4, shared by other developmentally regulated molecules implicated in parasite virulence. Functional complementation of a Leishmania donovani LPG-defective mutant (OB1) accumulating a truncated LPG containing only the Manα1-PO4 residue of the first repeat unit identified LPG3, the Leishmania homolog of the mammalian endoplasmic reticulum (ER) chaperone GRP94. LPG3 resembles GRP94, as it localizes to the parasite ER, and lpg3- mutants show defects including down-regulation of surface GPI-anchored proteins and mild effects on other glycoconjugates. LPG3 binds cellular proteins and its Leishmania infantum GRP94 ortholog is highly immunogenic, suggesting a potential role in directing the immune response. However, null lpg3- mutants grow normally, are completely defective in the synthesis of phosphoglycans, and the LPG3 mRNA is regulated developmentally but not by stress or heat. Thus the role of LPG3/GRP94 in Leishmania metabolism differs significantly from other eukaryotes. Like the other glycoconjugate synthetic pathways in this parasite, its activity is focused on molecules implicated in virulence rather than viability.

Original languageEnglish
Pages (from-to)4458-4469
Number of pages12
JournalEMBO Journal
Volume21
Issue number17
DOIs
StatePublished - Sep 2 2002

Keywords

  • GPI-anchored molecules
  • Glycoconjugate biosynthesis
  • Lipophosphoglycan
  • Parasite virulence
  • Trypanosomatid protozoan

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