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Vol. 12, Issue 8, 2364-2377, August 2001
and
*Department of Biochemistry and Molecular Biology, and The cell surface of the human parasite Leishmania
mexicana is coated with glycosylphosphatidylinositol
(GPI)-anchored macromolecules and free GPI glycolipids. We have
investigated the intracellular trafficking of green fluorescent
protein- and hemagglutinin-tagged forms of
dolichol-phosphate-mannose synthase (DPMS), a key enzyme in GPI
biosynthesis in L. mexicana promastigotes. These
functionally active chimeras are found in the same subcompartment of
the endoplasmic reticulum (ER) as endogenous DPMS but are degraded as
logarithmically growing promastigotes reach stationary phase,
coincident with the down-regulation of endogenous DPMS activity and GPI
biosynthesis in these cells. We provide evidence that these chimeras
are constitutively transported to and degraded in a novel
multivesicular tubule (MVT) lysosome. This organelle is a terminal
lysosome, which is labeled with the endocytic marker FM 4-64, contains
lysosomal cysteine and serine proteases and is disrupted by
lysomorphotropic agents. Electron microscopy and subcellular
fractionation studies suggest that the DPMS chimeras are transported
from the ER to the lumen of the MVT via the Golgi apparatus and a
population of 200-nm multivesicular bodies. In contrast, soluble ER
proteins are not detectably transported to the MVT lysosome in either
log or stationary phase promastigotes. Finally, the increased
degradation of the DPMS chimeras in stationary phase promastigotes
coincides with an increase in the lytic capacity of the MVT lysosome
and changes in the morphology of this organelle. We conclude that
lysosomal degradation of DPMS may be important in regulating the
cellular levels of this enzyme and the stage-dependent biosynthesis of the major surface glycolipids of these parasites.
the Plant
Cell Biology Research Centre, School of Botany, The
University of Melbourne, Victoria 3010, Australia
These authors contributed equally to this work.
§
Corresponding author. E-mail address:
malcolmm{at}unimelb.edu.au.
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