title: Physiological relevance of sphingolipid activator proteins in cultured human fibroblasts.
abstract: The physiological degradation of several membrane-bound glycosphingolipids (GSLs) by water-soluble lysosomal exohydrolases requires the assistance of sphingolipid activator proteins (SAPs). Four of these SAPs are synthesized from a single precursor protein (prosaposin). Inherited deficiency of this precursor results in a rare disease in humans with an accumulation of ceramide (Cer) and glycolipids such as glucosylceramide and lactosylceramide (LacCer). In a previous study, we have shown that human SAP-D stimulates the lysosomal degradation of Cer in precursor deficient cells. In order to study the role of SAPs (or saposins) A-D in cellular GSL catabolism, we recently investigated the catabolism of exogenously added [(3)H]labeled ganglioside GM1, Forssman lipid, and endogenously [(14)C]labeled GSLs in SAP-precursor deficient human fibroblasts after the addition of recombinant SAP-A, -B, -C and -D. We found that activator protein deficient cells are still able to slowly degrade gangliosides GM1 and GM3, Forssman lipid and globotriaosylceramide to a significant extent, while LacCer catabolism critically depends on the presence of SAPs. The addition of either of the SAPs, SAP-A, SAP-B or SAP-C, resulted in an efficient hydrolysis of LacCer.
authors.affiliation: Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany.
authors.forename: Farsaneh
authors.initials: F
authors.lastname: Sadeghlar
authors.forename: Natascha
authors.initials: N
authors.lastname: Remmel
authors.forename: Bernadette
authors.initials: B
authors.lastname: Breiden
authors.forename: Ralf
authors.initials: R
authors.lastname: Klingenstein
authors.forename: Guenter
authors.initials: G
authors.lastname: Schwarzmann
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000378:metabolism; D005915:Globosides / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D049231:Saposins; D049128:Sphingolipid Activator Proteins; D014281:Trihexosylceramides / Q000378:metabolism
chemical_list: D005679:G(M3) Ganglioside; D005915:Globosides; D006023:Glycoproteins; D006028:Glycosphingolipids; C483345:PSAP protein, human; D049231:Saposins; D049128:Sphingolipid Activator Proteins; D014281:Trihexosylceramides; D005677:G(M1) Ganglioside; C010163:Forssman glycolipid; C018549:globotriaosylceramide