Saposin C Is Required for Normal Resistance of Acid β-Glucosidase to Proteolytic Degradation

Sun, Ying; Qi, Xiaoyang; Grabowski, Gregory A.

doi:10.1074/jbc.m302752200

Cited by 69 publications

(75 citation statements)

References 43 publications

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“…Moreover, a recent work indicates that Sap C is required for GCase resistance to proteolytic degradation in the cells (38). The instability of GCase in NPC1 fibroblasts cannot be attributed to a low amount of Sap C, because we found that high levels of prosaposin are synthesized and converted to Sap C in these cells (see Fig.…”

Section: Figmentioning

confidence: 54%

Glucosylceramidase Mass and Subcellular Localization Are Modulated by Cholesterol in Niemann-Pick Disease Type C

Salvioli

Scarpa

Ciaffoni

et al. 2004

Journal of Biological Chemistry

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Niemann-Pick disease type C (NPC) is characterized by the accumulation of cholesterol and sphingolipids in the late endosomal/lysosomal compartment. The mechanism by which the concentration of sphingolipids such as glucosylceramide is increased in this disease is poorly understood. We have found that, in NPC fibroblasts, the cholesterol storage affects the stability of glucosylceramidase (GCase), decreasing its mass and activity; a reduction of cholesterol raises the level of GCase to nearly normal values. GCase is activated and stabilized by saposin C (Sap C) and anionic phospholipids. Here we show by immunofluorescence microscopy that in normal fibroblasts, GCase, Sap C, and lysobisphosphatidic acid (LBPA), the most abundant anionic phospholipid in the endolysosomal system, reside in the same intracellular vesicular structures. In contrast, the colocalization of GCase, Sap C, and LBPA is markedly impaired in NPC fibroblasts but can be reestablished by cholesterol depletion. These data show for the first time that the level of cholesterol modulates the interaction of GCase with its protein and lipid activators, namely Sap C and LBPA, regulating the GCase activity and stability.

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Section: Figmentioning

confidence: 54%

Glucosylceramidase Mass and Subcellular Localization Are Modulated by Cholesterol in Niemann-Pick Disease Type C

Salvioli

Scarpa

Ciaffoni

et al. 2004

Journal of Biological Chemistry

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“…This suggests that the increase in GCase activity is likely to be regulated through other components of the lysosomal pathway, such as saponin C, which has been shown to both activate and stabilize GCase 29, 30…”

Section: Discussionmentioning

confidence: 99%

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Migdalska‐Richards

Daly

Bézard

et al. 2016

Annals of Neurology

161

138

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ObjectiveGaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α‐synuclein and phosphorylated α‐synuclein protein levels in mice.MethodsMice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α‐synuclein and phosphorylated α‐synuclein protein levels.ResultsAmbroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild‐type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α‐synuclein. Furthermore, in the mice overexpressing human α‐synuclein, ambroxol treatment decreased both α‐synuclein and phosphorylated α‐synuclein protein levels.InterpretationOur work supports the proposition that ambroxol should be further investigated as a potential novel disease‐modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α‐synuclein and phosphorylated α‐synuclein protein levels. Ann Neurol 2016;80:766–775

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“…Because our liposome sedimentation and crosslinking studies suggest that CD1c-Fc is recruited to the liposome surface by membrane-associated SapC molecules, we hypothesized that CD1c-Fc molecules could access liposome-embedded lipid antigens by co-opting a similar membrane-associated mechanism used by lysosomal hydrolases to mediate GSL degradation (19,22,23,26). In support of this hypothesis, our results demonstrate that only liposome-associated SapC molecules had the capacity to load CD1c-Fc and evoke T-cell activation when the antigen is provided in a membrane-bound form (Fig.…”

Section: Resultsmentioning

confidence: 99%

Saposins utilize two strategies for lipid transfer and CD1 antigen presentation

León

Tatituri

Grenha

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Transferring lipid antigens from membranes into CD1 antigenpresenting proteins represents a major molecular hurdle necessary for T-cell recognition. Saposins facilitate this process, but the mechanisms used are not well understood. We found that saposin B forms soluble saposin protein-lipid complexes detected by native gel electrophoresis that can directly load CD1 proteins. Because saposin B must bind lipids directly to function, we found it could not accommodate long acyl chain containing lipids. In contrast, saposin C facilitates CD1 lipid loading in a different way. It uses a stable, membrane-associated topology and was capable of loading lipid antigens without forming soluble saposin-lipid antigen complexes. These findings reveal how saposins use different strategies to facilitate transfer of structurally diverse lipid antigens. . Although the molecular mechanisms governing MHC class I and II peptide loading are well appreciated, the mechanisms of CD1 lipid loading remain poorly understood. In the case of MHC class I molecules, proteasome-derived peptides are loaded onto MHC class I molecules by proteins of the peptide loading complex whose components include calnexin, calreticulin, ERp57, tapasin, and TAP (2). MHC class II molecules are loaded in endosomal compartments, where HLA-DM facilitates the exchange of the class II associated invariant peptide for high-affinity peptides derived from lysosomal processing of exogenous proteins (3, 4). The capacity of the MHC class I and II processing and antigen loading mechanisms are major factors determining which peptides are antigenic. In contrast to MHC-presented peptides, CD1-restricted lipid antigens are amphipathic molecules that are typically embedded in cellular membranes or micelles (5) and thus may be largely inaccessible to luminal proteins. Given the nonpolar component of lipids, mobilization of membrane-derived lipids across an aqueous endocytic environment likely requires extraction from membranes and, in most cases, transport across aqueous biological buffers into the lipid-binding grooves of CD1 molecules. These related processes are predicted to have unfavorable dissolution energetics and is unlikely to occur efficiently without the assistance of lipid-transfer proteins or other molecular mediators (6, 7).Recent studies have shown that saposins, a family of small, nonenzymatic lipid-binding proteins, facilitate CD1 lipid loading in endosomal compartments (6,(8)(9)(10). To a relative extent, all saposins enhance CD1 lipid loading in cellular and in vitro assays, but they appear to have a differential capacity to load particular lipids into individual CD1 isoforms. In one study, saposin B (SapB) was shown to facilitate α-galactosylceramide (αGalCer) loading onto human CD1d molecules more efficiently than other saposin isoforms (9). In cellular studies, saposin C (SapC), but not other saposins, restored CD1b presentation of long-chain mycobacterial antigens in saposin-deficient antigen presenting cells (8). Furthermore, direct visualization of lipid-l...

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Saposin C Is Required for Normal Resistance of Acid β-Glucosidase to Proteolytic Degradation

Cited by 69 publications

References 43 publications

Glucosylceramidase Mass and Subcellular Localization Are Modulated by Cholesterol in Niemann-Pick Disease Type C

Glucosylceramidase Mass and Subcellular Localization Are Modulated by Cholesterol in Niemann-Pick Disease Type C

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Saposins utilize two strategies for lipid transfer and CD1 antigen presentation

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