Recycling Compartments and the Internal Vesicles of Multivesicular Bodies Harbor Most of the Cholesterol Found in the Endocytic Pathway

Möbius, Wiebke; Donselaar, Elly van; Ohno‐Iwashita, Yoshiko; Shimada, Yukiko; Heijnen, Harry F. G.; Slot, Jan W.; Geuze, Hans J.

doi:10.1034/j.1600-0854.2003.00072.x

Cited by 400 publications

(379 citation statements)

References 77 publications

(93 reference statements)

Supporting

Mentioning

346

Contrasting

Unclassified

Order By: Relevance

“…Both LBPA and cholesterol are enriched in the internal membranes. However, whereas LBPA is enriched in lysosomes, cholesterol is depleted [44]. In some cases, these vesicles fuse back with the outer membrane [45].…”

Section: Discussionmentioning

confidence: 99%

Membrane lipids and vesicular traffic

Meer

Sprong

2004

Current Opinion in Cell Biology

157

View full text Add to dashboard Cite

Lipids were long considered to be passive passengers of carrier vesicles with the single role of sealing the transport container. We now know that specific phospholipids are required for efficient fusion, while others facilitate budding and fission. Moreover, the various polyphosphoinositides assist in the recruitment from the cytosol of proteins of the transport machinery. Finally, the segregation of membrane lipids into different fluid phases appears to serve as a 'lipid raft' mechanism for protein sorting at various stages of the secretory and endocytic pathways. The current challenge is to understand how proteins control the metabolism and subcellular localization, and thereby the activity, of the various lipids.

show abstract

Section: Discussionmentioning

confidence: 99%

Membrane lipids and vesicular traffic

Meer

Sprong

2004

Current Opinion in Cell Biology

157

View full text Add to dashboard Cite

show abstract

“…In wild type cells, the bulk of cholesterol normally occupies early, not late, endocytic and recycling compartments (38,55).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Accumulation Sequesters Rab9 and Disrupts Late Endosome Function in NPC1-deficient Cells

Ganley

Pfeffer

2006

Journal of Biological Chemistry

106

127

View full text Add to dashboard Cite

Niemann-Pick type C disease is an autosomal recessive disorder that leads to massive accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. To understand how cholesterol accumulation influences late endosome function, we investigated the effect of elevated cholesterol on Rab9-dependent export of mannose 6-phosphate receptors from this compartment. Endogenous Rab9 levels were elevated 1.8-fold in Niemann-Pick type C cells relative to wild type cells, and its half-life increased 1.6-fold, suggesting that Rab9 accumulation is caused by impaired protein turnover. Reduced Rab9 degradation was accompanied by stabilization on endosome membranes, as shown by a reduction in the capacity of Rab9 for guanine nucleotide dissociation inhibitor-mediated extraction from Niemann-Pick type C membranes. Cholesterol appeared to stabilize Rab9 directly, as liposomes loaded with prenylated Rab9 showed decreased extractability with increasing cholesterol content. Rab9 is likely sequestered in an inactive form on Niemann-Pick type C membranes, as cation-dependent mannose 6-phosphate receptors were missorted to the lysosome for degradation, a process that was reversed by overexpression of GFPtagged Rab9. In addition to using primary fibroblasts isolated from Niemann-Pick type C patients, RNA interference was utilized to recapitulate the disease phenotype in cultured cells, greatly facilitating the analysis of cholesterol accumulation and late endosome function. We conclude that cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking. Niemann-Pick type C (NPC)2 is an autosomal recessive, neurodegenerative disorder. A hallmark of NPC is the massive accumulation of cholesterol and glycosphingolipids within late endosomes and lysosomes (reviewed in Refs. 1-3). In normal cells, endocytosed low density lipoproteins are delivered to endosomes, where they are hydrolyzed and free cholesterol is released. This cholesterol is transported rapidly out of endosomes to the plasma membrane and endoplasmic reticulum (4, 5). In NPC cells, the cholesterol does not exit the endocytic pathway and it accumulates within lysosomes.Approximately 95% of NPC patients harbor mutations in the NPC1 gene that encodes a large, late endosomal protein with 13 transmembrane domains (6 -8). Although NPC1 binds cholesterol weakly (9), the precise function of NPC1 is unknown; it may be involved in cholesterol export from late endosomes (10). The remainder of NPC patients carry mutations in the NPC2 gene that encodes a small, soluble protein present in the lumen of late endosomes and lysosomes (11). Unlike NPC1, NPC2 binds cholesterol with high affinity (12), but like NPC1, its precise role is unclear.Late endosomes act as sorting stations to deliver endocytosed molecules to lysosomes for degradation, while at the same time, retrieving other classes of proteins and lipids for transport back to non-degradative compartments. Mannose 6-phos...

show abstract

“…As an alternative mechanism, protein coats may form on the limiting membrane of MVEs to stabilize it, and the internal vesicles might be formed by generating patches of lipid in the cytoplasmic leaflet of uncoated membrane that favor negative curvature and cause the membrane to invaginate (275). The internal vesicles of MVEs are enriched in cholesterol and lysobisphosphatidic acid (186,187,241), in-dicating that sorting of lipids does occur during their formation.…”

Section: B Ptdins(3)p On Endosomesmentioning

confidence: 99%

Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

263

267

View full text Add to dashboard Cite

Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

show abstract

Recycling Compartments and the Internal Vesicles of Multivesicular Bodies Harbor Most of the Cholesterol Found in the Endocytic Pathway

Cited by 400 publications

References 77 publications

Membrane lipids and vesicular traffic

Membrane lipids and vesicular traffic

Cholesterol Accumulation Sequesters Rab9 and Disrupts Late Endosome Function in NPC1-deficient Cells

Phosphoinositides in Constitutive Membrane Traffic

Contact Info

Product

Resources

About