The Kinetics of Mannose 6-Phosphate Receptor Trafficking in the Endocytic Pathway in HEp-2 Cells: The Receptor Enters and Rapidly Leaves Multivesicular Endosomes without Accumulating in a Prelysosomal Compartment

Hirst, Jennifer; Futter, Clare E.; Hopkins, Colin R.

doi:10.1091/mbc.9.4.809

Cited by 63 publications

(48 citation statements)

References 27 publications

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“…However, in human fibroblasts we did not find M6PR in the NPC1-containing vesicles that we consider to be late endosomes (10). In other cells, including Hep-2 cells, M6PR was also not visualized in late endosomes at steady states and most of the receptor was found within the transGolgi network and in vacuolar structures in the peripheral cytoplasm (31). We found comparable locations for M6PR in normal fibroblasts (Fig.…”

Section: Cellular Cholesterol Uptake Enriches the Npc1 Content Of Latsupporting

confidence: 50%

Sterol-modulated Glycolipid Sorting Occurs in Niemann-Pick C1 Late Endosomes

Zhang¹,

Dwyer²,

Neufeld³

et al. 2001

Journal of Biological Chemistry

105

115

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The Niemann-Pick C1 (NPC1) protein and endocytosed low density lipoprotein (LDL)-derived cholesterol were shown to enrich separate subsets of vesicles containing lysosomal associated membrane protein 2. Localization of Rab7 in the NPC1-containing vesicles and enrichment of lysosomal hydrolases in the cholesterolcontaining vesicles confirmed that these organelles were late endosomes and lysosomes, respectively. Lysobisphosphatidic acid, a lipid marker of the late endosomal pathway, was found in the cholesterol-enriched lysosomes. Recruitment of NPC1 to Rab7 compartments was stimulated by cellular uptake of cholesterol. The NPC1 compartment was shown to be enriched in glycolipids, and internalization of GalNAc␤1-4[NeuAc␣2-3]Gal␤1-4Glc␤1-1-ceramide (G M2 ) into endocytic vesicles depends on the presence of NPC1 protein. The glycolipid profiles of the NPC1 compartment could be modulated by LDL uptake and accumulation of lysosomal cholesterol. Expression in cells of biologically active NPC1 protein fused to green fluorescent protein revealed rapidly moving and flexible tubular extensions emanating from the NPC1-containing vesicles. We conclude that the NPC1 compartment is a dynamic, sterolmodulated sorting organelle involved in the trafficking of plasma membrane-derived glycolipids as well as plasma membrane and endocytosed LDL cholesterol.

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Section: Cellular Cholesterol Uptake Enriches the Npc1 Content Of Latsupporting

confidence: 50%

Sterol-modulated Glycolipid Sorting Occurs in Niemann-Pick C1 Late Endosomes

Zhang¹,

Dwyer²,

Neufeld³

et al. 2001

Journal of Biological Chemistry

105

115

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“…The following NCBI RefSeq records were used for SPE-39 orthologues: human (NP_071350. endosomes, which are locations from which M6PR returns back to the Golgi complex (Klumperman et al, 1993;Hirst et al, 1998;Gissen et al, 2004;Tortorella et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Prior work has revealed that M6PR moves between the Golgi and endosomes along diverse recycling pathways (Ghosh et al, 2003;Bonifacino and Rojas, 2006). Recycling endosomes and late endosomes are among the endocytic compartments from which M6PR returns back to the Golgi complex (Klumperman et al, 1993;Hirst et al, 1998;Lin et al, 2004;Tortorella et al, 2007). Consequently, we analyzed the subcellular distribution of the mannose-6-phosphate receptor (M6PR) in control and hSPE-39 downregulated cells.…”

Section: Hspe-39 Is Required For M6pr-mediated Transportmentioning

confidence: 99%

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Zhu

Salazar²,

Zlatic³

et al. 2009

MBoC

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Yeast and animal homotypic fusion and vacuole protein sorting (HOPS) complexes contain conserved subunits, but HOPS-mediated traffic in animals might require additional proteins. Here, we demonstrate that SPE-39 homologues, which are found only in animals, are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. Although Caenorhabditis elegans spe-39 mutants were initially identified as having abnormal vesicular biogenesis during spermatogenesis, we show that these mutants also have disrupted processing of endocytosed proteins in oocytes and coelomocytes. C. elegans SPE-39 interacts in vitro with both VPS33A and VPS33B, whereas RNA interference of VPS33B causes spe-39-like spermatogenesis defects. The human SPE-39 orthologue C14orf133 also interacts with VPS33 homologues and both coimmunoprecipitates and cosediments with other HOPS subunits. SPE-39 knockdown in cultured human cells altered the morphology of syntaxin 7-, syntaxin 8-, and syntaxin 13-positive endosomes. These effects occurred concomitantly with delayed mannose 6-phosphate receptor-mediated cathepsin D delivery and degradation of internalized epidermal growth factor receptors. Our findings establish that SPE-39 proteins are a previously unrecognized regulator of lysosomal delivery and that C. elegans spermatogenesis is an experimental system useful for identifying conserved regulators of metazoan lysosomal biogenesis. INTRODUCTIONLysosome biogenesis is mediated by multiple vesicular budding and fusion events that deliver components between subcellular compartments (Luzio et al., 2003). In Saccharomyces cerevisiae, vesicular fusion at the vacuole (the yeast equivalent of lysosomes) requires the homotypic fusion and vacuole protein sorting (HOPS) complex, which regulates vesicle docking through its interaction with soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) and the Rab protein Ypt7p Sato et al., 2000;Wurmser et al., 2000). The yeast HOPS complex contains class C Vps proteins Vps11p, Vps16p, Vps18p, and Vps33p (Rieder and Emr, 1997) and class B Vps proteins Vps39p and Vps41p (Seals et al., 2000;Wurmser et al., 2000). In addition to vesicular fusion at the vacuole, the class C Vps proteins also function in Golgi-to-endosome transport and other steps in vacuolar delivery pathways (Srivastava et al., 2000;Peterson and Emr, 2001;Subramanian et al., 2004;Peplowska et al., 2007). Involvement of the class C Vps proteins at multiple stages has also been reported in mammalian cells (Kim et al., 2003;Richardson et al., 2004). Vesicular trafficking to the lysosome has been extensively described in yeast (Bowers and Stevens, 2005), but it is also known that this process is more complex in metazoans (Dell'Angelica, 2004). Yeast only has lysosomes of a single type, whereas animals have lysosomes and lysosome-related organelles that are functionally diverse. This diversity is evident when comparing th...

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“…Significantly, they also show that the GFP moiety is delivered to the lumen of the MVT consistent with the finding that this protein is rapidly degraded when promastigotes are incubated in low pH medium. In yeast and animal cells, many membrane proteins are targeted to the vacuole/lysosome lumen via the recently described MVB pathway (Hirst et al, 1998;Kobayashi et al, 1998;Odorizzi et al, 1998;). In this pathway, membrane proteins destined for lysosomal degradation are transported from either the Golgi apparatus or the plasma membrane to the limiting membrane of late endosomes and subsequently incorporated into microinvaginating vesicles that are released into the luminal compartment.…”

Section: Discussionmentioning

confidence: 99%

Regulated Degradation of an Endoplasmic Reticulum Membrane Protein in a Tubular Lysosome inLeishmania mexicana

Mullin¹,

Foth

Ilgoutz³

et al. 2001

MBoC

163

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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 dolicholphosphate-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.

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The Kinetics of Mannose 6-Phosphate Receptor Trafficking in the Endocytic Pathway in HEp-2 Cells: The Receptor Enters and Rapidly Leaves Multivesicular Endosomes without Accumulating in a Prelysosomal Compartment

Cited by 63 publications

References 27 publications

Sterol-modulated Glycolipid Sorting Occurs in Niemann-Pick C1 Late Endosomes

Sterol-modulated Glycolipid Sorting Occurs in Niemann-Pick C1 Late Endosomes

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Regulated Degradation of an Endoplasmic Reticulum Membrane Protein in a Tubular Lysosome inLeishmania mexicana

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