Only sphingolipid activator protein B (SAP‐B or saposin B) stimulates the degradation of globotriaosylceramide by recombinant human lysosomal α‐galactosidase in a detergent‐free liposomal system

Kase, Ryoichi; Bierfreund, Uwe; Klein, Andreas; Kolter, Thomas; Itoh, Kohji; Suzuki, Minoru; Hashimoto, Yasuhiro; Sandhoff, Konrad; Sakuraba, Hitoshi

doi:10.1016/0014-5793(96)00863-0

Cited by 15 publications

(8 citation statements)

References 17 publications

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“…Of the four saposins, the crucial role of sap B in the solubilization of some sphingolipid substrates (e.g. sulfatide and globotriaosylceramide [17]) has been clearly established (for review, see [18]), and recently the role of sap D in the activation of ceramide hydrolysis by acid ceramidase has been recognized [3, 16, 19].…”

Section: Introductionmentioning

confidence: 99%

Saposins (sap) A and C activate the degradation of galactosylceramide in living cells

et al. 1997

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In loading tests using galactosylceramide which had been labelled with tritium in the ceramide moiety, living skin fibroblast lines derived from the original prosaposin-deficient patients had a markedly reduced capacity to degrade galactosylceramide. The hydrolysis of galactosylceramide could be partially restored in these cells, up to about half the normal rate, by adding pure saposin A, pure saposin C, or a mixture of these saposins to the culture medium. By contrast, saposins B and D had little effect on galactosylceramide hydrolysis in the prosaposin-deficient cells. Cells from P-galactocerebrosidasedeficient (Krabbe) patients had a relatively high residual galactosylceramide degradation, which was similar to the rate observed for prosaposin-deficient cells in the presence of saposin A or C. An SV40-transformed fibroblast line from the original saposin C-deficient patient, where saposin A is not affected, showed normal degradation of galactosylceramide. The findings support the hypothesis, which was deduced originally from in vitro experiments, that saposins A and C are the in vivo activators of galactosylceramide degradation. Although the results with saposin C-deficient fibroblasts suggest that the presence of only saposin A allows galactosylceramide breakdown to proceed at a normal rate in fibroblasts, it remains to be determined whether saposins A and C can substitute for each other with respect to their effects on galactosylceramide metabolism in the whole organism. © 1997 Federation of European Biochemical Societies.

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Section: Introductionmentioning

confidence: 99%

Saposins (sap) A and C activate the degradation of galactosylceramide in living cells

et al. 1997

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“…Neither saposins nor G M2 A assisted the loading of Galα1,2αGC (22). However, because Galα1,2αGC needs processing into αGC by α-glycosidase A, a saposin-dependent enzyme (34), defective presentation of Galα1,2αGC by SAP −/− cells (Fig. 2) is likely a result of defective processing.…”

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confidence: 99%

Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins

Zhou

Cantu

Sagiv

et al. 2004

Science

296

304

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It is now established that CD1 molecules present lipid antigens to T cells, although it is not clear how the exchange of lipids between membrane compartments and the CD1 binding groove is assisted. We report that mice deficient in prosaposin, the precursor to a family of endosomal lipid transfer proteins (LTP), exhibit specific defects in CD1d-mediated antigen presentation and lack Vα14 NKT cells. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1. Transient complexes between CD1, lipid, and LTP suggested a "tug-of-war" model in which lipid exchange between CD1 and LTP is on the basis of their respective affinities for lipids. LTPs constitute a previously unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens.CD1 molecules have evolved a unique hydrophobic binding groove that binds lipid antigens in both the secretory and endosomal compartments for presentation to T lymphocytes (1). In mice, the main population of CD1-restricted T cells, called Vα14 NKT cells, express a † These authors contributed equally to this work. To whom correspondence should be addressed. abendela@bsd.uchicago.edu (A.B.); lteyton@scripps.edu (L.T.). * These authors contributed equally to this work. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptsemi-invariant Vα14-Jα18/Vβ8 T cell receptor (TCR). These cells exhibit reactivity against CD1d in combination with endogenous ligands (2) that can be mimicked by α-galactosylceramide (αGC) (3). This population is conserved among mammalian species and regulates immune responses (4, 5). Like human CD1b-restricted T cells specific for mycobacterial glycolipids (6), Vα14 NKT cells are dependent on endosomal trafficking of CD1d for natural antigen recognition (7-10). Other endogenous or exogenous antigens do not require endosomal trafficking, however, suggesting that loading may be achieved in distinct cellular compartments depending on the nature of the antigen (9,11,12). CD1 endosomal trafficking is tightly controlled by cytoplasmic tail-encoded tyrosine-containing motifs binding adaptor protein 2 and 3 (AP-2 and AP-3) complexes, as well as by association with the invariant chain (Ii) or Ii/major histocompatibility (MHC) class II complexes (13-16).Because lipids are integral membrane components that might require lipid transfer proteins (LTP) (17) for extraction, we investigated whether various families of LTP might assist antigen presentation. We focused on the Vα14 NKT cell endosomal-dependent system to test the possible involvement of LTPs localized in the endocytic pathway, such as saposins (18) (Fig. 1D). These findings demonstrate a selective defect in the development of Vα14 NKT cells in the absence of prosaposin.Many NKT cell hybridomas can be activated in vitro to release interleukin-2 (IL-2) by coculture with fresh CD1d-expressing cells, such as thymocytes, which are...

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“…The catabolic pathway of GSLs needs different cofactors and enzymes. The AGAL enzyme in its active form requires saposin B to start its activity on substrate that is Gb3 [12]. The insufficient activity of AGAL to catalyze the hydrolytic cleavage of the terminal galactose from Gb3 causes the excessive accumulation of globotriaosylsphingosine (lyso-Gb3) in kidney, lungs and erythrocytes [13,14].…”

Section: α-Galactosidase Amentioning

confidence: 99%

Fabry Disease: from Diagnosis to Therapy

Shafqat¹,

Shahzad²

2012

IOSJPBS

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Fabry disease (FD) is an accelerating, X-linked hereditary disorder of glycosphingolipid metabolism which occurs due to improper lysosomal α-galactosidase A activity. Its pan-ethnic and the annually reported occurrence may underestimate the true frequency of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristics like cardiovascular (cardiomyopathy), cutaneous (angiokeratoma), renal (kidney failure), neurological (pain), cerebrovascular and cochleo-vestibular signs of the disease while heterozygous females have similar symptoms ranging from very mild to severe. Incomplete action of lysosomal α-galactosidase A results in gradual increase of globotriaosylceramide within lysosomes, supposed to set off a flow of cellular events. Enzyme analysis may occasionally help to detect heterozygote but in females results are often questionable because of random X-chromosomal inactivation that obligates the molecular testing (genotyping). Due to ethical reasons determination of enzyme activity through prenatal diagnosis is carried out only in male's fetus. The subsistence of atypical variants and the unavailability of a specific therapy complicate the genetic counseling. Enzyme replacement therapy (ERT) is the only specific therapeutic option that introduced recombinant human α-galactosidase A. End stage renal disease and critical cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females. Oral therapy drives the research forward into active site specific chaperones. Adjunctive therapy of ERT with chemical chaperone therapy can arrest disease succession.

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Only sphingolipid activator protein B (SAP‐B or saposin B) stimulates the degradation of globotriaosylceramide by recombinant human lysosomal α‐galactosidase in a detergent‐free liposomal system

Cited by 15 publications

References 17 publications

Saposins (sap) A and C activate the degradation of galactosylceramide in living cells

Saposins (sap) A and C activate the degradation of galactosylceramide in living cells

Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins

Fabry Disease: from Diagnosis to Therapy

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