Trends in Cell Biology
ForumJamming the endosomal system: lipid rafts and lysosomal storage diseases
Section snippets
Lysobisphosphatidic acid-rich membranes of late endosomes
One lipid that is enriched in late endosomes is lysobisphosphatidic acid (LBPA), which is a characteristic molecule of this degradative organelle in the endocytic pathway15. LBPA is localized to the complex system of membranes present in the lumen of late endosomes and is an abundant constituent of these membranes (4–17 mole percent)15. A unique property of LBPA is that the lipid is a poor substrate for phospholipases and hence is resistant to lysosomal enzyme degradation16. The lipid is
Lipid storage diseases
A relatively large subgroup of lysosomal storage diseases are caused by the accumulation of lipids in late endosomes or lysosomes21., 22.. The Niemann–Pick (NP) syndrome, which is now known to have more than one cause23., 24., is of particular interest; NP types A and B are characterized by sphingomyelin accumulation, whereas cholesterol typically accumulates in the third form, NPC. In NPC, accumulation of cholesterol in degradative compartments of the endocytic pathway is apparently due to a
A unified working hypothesis
These findings led us to formulate a model for the normal handling of lipid rafts in the endocytic pathway, which might serve to clarify some of the problems associated with lipid storage diseases. The basis of our postulate is that the amounts of raft lipids tolerated by late endosomes are limited. In some cell types, with a high hydrolytic capacity, sphingolipids might be transported to late endosomes and then be rapidly degraded after incorporation into LBPA-internal membranes, where the
Perspectives
Beyond the striking similarities in raft lipid redistribution in lipid storage diseases, great variations are observed in the types of affected tissues and in the clinical pictures. These variations might be caused by cell-type-specific expression of sphingolipids, as well as by differences in the residual activity of an affected enzyme (threshold theory), which might lead to an adult (high residual activity) or infantile (low residual activity) onset of the disease (discussed in Ref. 22).
References (36)
Glycosphingolipids are not essential for formation of detergent-resistant membrane rafts in melanoma cells. Methyl-beta-cyclodextrin does not affect cell surface transport of a GPI-anchored protein
J. Biol. Chem.
(1999)Caveolae and caveolins
Curr. Opin. Cell Biol.
(1996)- et al.
Membrane transport in the endocytic pathway
Curr. Opin. Cell Biol.
(1995) Lipids and lipid domains in endocytic membrane traffic
Semin. Cell Dev. Biol.
(1998)The role of endosomes and lysosomes in MHC class II functioning
Immunol. Today
(1998)Novel stereochemical configuration in lysobisphosphatidic acid of cultured BHK cells
Chem. Phys. Lipids
(1974)Lysosomal degradation on vesicular membrane surfaces. Enhanced glucosylceramide degradation by lysosomal anionic lipids and activators
J. Biol. Chem.
(1998)Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann-Pick disease type C
Brain Dev.
(1998)Broad screening test for sphingolipid-storage diseases
Lancet
(1999)- et al.
The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor
Cell
(1997)
Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol
J. Lipid Res.
Functions of lipid rafts in biological membranes
Annu. Rev. Cell Dev. Biol.
Functional rafts in cell membranes
Nature
Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells
J. Cell Biol.
Cholesterol-dependent retention of GPI-anchored proteins in endosomes
EMBO J.
The recycling endosome of MDCK cells is a mildly acidic compartment rich in raft components
Mol. Biol. Cell
Isolation and biochemical characterization of organelles from the yeast, Saccharomyces cerevisiae
Yeast
Large-scale co-aggregation of fluorescent lipid probes with cell surface proteins
J. Cell Biol.
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