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PMID: 9707421 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor-related protein (LRP).

The EMBO journal ·Vol. 17 ·No. 16 ·1998-08-17 ·Pages 4617-25

Hiesberger T, Hüttler S, Rohlmann A, Schneider W, Sandhoff K, Herz J

Abstract

Sphingolipid activator proteins SAP-A, -B, -C and -D (also called saposins) are generated by proteolytic processing from a 73 kDa precursor and function as obligatory activators of lysosomal enzymes involved in glycosphingolipid metabolism. Although the SAP precursor can be recognized by the mannose-6-phosphate (M-6-P) receptor and shuttled directly from the secretory pathway to the lysosome, a substantial fraction of newly synthesized precursor is secreted from the cell where it may participate in sphingolipid transport and signaling events. Re-uptake of the secreted precursor is mediated by high-affinity cell surface receptors that are apparently distinct from the M-6-P receptor. We found that the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic receptor that is expressed on most cells, can mediate cellular uptake and lysosomal delivery of SAP precursor. Additional in vivo experiments in mice revealed that the mannose receptor system on macrophages also participates in precursor internalization. We conclude that SAP precursor gains entry into cells by at least three independent receptor mechanisms including the M-6-P receptor, the mannose receptor and LRP.

MeSH Terms
Animals Base Sequence Cell Line DNA Primers Endocytosis Glycoproteins/metabolism Humans Low Density Lipoprotein Receptor-Related Protein-1 Lysosomes/metabolism Mice Protein Precursors/genetics,metabolism Receptors, Cell Surface/metabolism Receptors, Immunologic/metabolism Receptors, LDL/metabolism Signal Transduction
Chemicals
DNA Primers Glycoproteins Low Density Lipoprotein Receptor-Related Protein-1 Protein Precursors Receptors, Cell Surface Receptors, Immunologic Receptors, LDL
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hiesberger T
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA.
Hüttler S
Rohlmann A
Schneider W
Sandhoff K
Herz J
References (41)
41 references, click to expand
  1. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein.
    J Biol Chem. 1990 Jun 25;265(18):10771-9 PMID: 2355022
  2. Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4778-81 PMID: 9114068
  3. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7422-6 PMID: 1502153
  4. Identification of prosaposin as a neurotrophic factor.
    Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9593-6 PMID: 7937812
  5. Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide.
    J Biol Chem. 1997 Jul 4;272(27):16862-7 PMID: 9201993
  6. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.
    J Biol Chem. 1991 Nov 5;266(31):21232-8 PMID: 1718973
  7. Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP-2 deficiency.
    Somat Cell Mol Genet. 1993 Jan;19(1):1-7 PMID: 8460394
  8. Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy.
    Am J Hum Genet. 1996 Jan;58(1):65-74 PMID: 8554069
  9. The biogenesis of lysosomes.
    Annu Rev Cell Biol. 1989;5:483-525 PMID: 2557062
  10. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease.
    Hum Genet. 1993 Sep;92(2):143-52 PMID: 8370580
  11. The subcellular localization of soluble and membrane-bound lysosomal enzymes in I-cell fibroblasts: a comparative immunocytochemical study.
    Eur J Cell Biol. 1985 Nov;39(1):179-89 PMID: 2935398
  12. Secretion of sphingolipid hydrolase activator precursor, prosaposin.
    Biochem Biophys Res Commun. 1991 Apr 30;176(2):668-74 PMID: 2025281
  13. A hydrophilic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo.
    J Neurochem. 1996 May;66(5):2197-200 PMID: 8780053
  14. Biosynthesis of lysosomal enzymes in fibroblasts. Phosphorylation of mannose residues.
    J Biol Chem. 1980 May 25;255(10):4946-50 PMID: 6989822
  15. Genetic deficiency in low density lipoprotein receptor-related protein confers cellular resistance to Pseudomonas exotoxin A. Evidence that this protein is required for uptake and degradation of multiple ligands.
    J Cell Sci. 1994 Mar;107 ( Pt 3):719-26 PMID: 8006085
  16. Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses.
    Eur J Pediatr. 1989 Oct;149(1):31-9 PMID: 2514102
  17. Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4611-5 PMID: 7753850
  18. Sustained somatic gene inactivation by viral transfer of Cre recombinase.
    Nat Biotechnol. 1996 Nov;14(11):1562-5 PMID: 9634821
  19. Identification of a variant of mucolipidosis III (pseudo-Hurler polydystrophy): a catalytically active N-acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes.
    Proc Natl Acad Sci U S A. 1981 Dec;78(12):7773-7 PMID: 6461005
  20. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins.
    Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810-4 PMID: 2762297
  21. Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphrenylglycoluril.
    Biochem Biophys Res Commun. 1978 Feb 28;80(4):849-57 PMID: 637870
  22. Metabolism of GM1 ganglioside in cultured skin fibroblasts: anomalies in gangliosidoses, sialidoses, and sphingolipid activator protein (SAP, saposin) 1 and prosaposin deficient disorders.
    Hum Genet. 1992 Jul;89(5):513-8 PMID: 1634229
  23. Binding and transport of gangliosides by prosaposin.
    Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11254-8 PMID: 1454804
  24. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells.
    Methods Enzymol. 1983;98:241-60 PMID: 6321901
  25. Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids.
    Hum Mol Genet. 1996 Jun;5(6):711-25 PMID: 8776585
  26. Immunocytochemical localization of sphingolipid activator protein 2 (SAP-2) in normal and SAP-deficient fibroblasts.
    Eur J Cell Biol. 1990 Feb;51(1):157-64 PMID: 2109697
  27. Saposins: structure, function, distribution, and molecular genetics.
    J Lipid Res. 1992 Sep;33(9):1255-67 PMID: 1402395
  28. Biochemistry of glycosphingolipid degradation.
    Clin Chim Acta. 1997 Oct 9;266(1):51-61 PMID: 9435988
  29. Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP )precursor in cultured human fibroblasts. Mannose 6-phosphate receptor-independent endocytosis of SAP precursor.
    J Biol Chem. 1996 Dec 13;271(50):32438-46 PMID: 8943309
  30. Insulin-like growth factor II receptor as a multifunctional binding protein.
    Nature. 1987 Sep 24-30;329(6137):301-7 PMID: 2957598
  31. Additional biochemical findings in a patient and fetal sibling with a genetic defect in the sphingolipid activator protein (SAP) precursor, prosaposin. Evidence for a deficiency in SAP-1 and for a normal lysosomal neuraminidase.
    Biochem J. 1992 Jul 15;285 ( Pt 2):481-8 PMID: 1637339
  32. Topology of glycosphingolipid degradation.
    Trends Cell Biol. 1996 Mar;6(3):98-103 PMID: 15157485
  33. Germ cell-somatic cell dichotomy of a low-density lipoprotein receptor gene family member in testis.
    DNA Cell Biol. 1997 Jan;16(1):35-43 PMID: 9022043
  34. Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants.
    J Clin Invest. 1998 Feb 1;101(3):689-95 PMID: 9449704
  35. The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.
    Hum Genet. 1991 Jun;87(2):211-5 PMID: 2066109
  36. Detection of a point mutation in sphingolipid activator protein-1 mRNA in patients with a variant form of metachromatic leukodystrophy.
    Biochem Biophys Res Commun. 1990 Jan 30;166(2):1017-23 PMID: 2302219
  37. Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease.
    FEBS Lett. 1991 Jun 17;284(1):57-9 PMID: 2060627
  38. A hypothesis for I-cell disease: defective hydrolases that do not enter lysosomes.
    Biochem Biophys Res Commun. 1972 Nov 15;49(4):992-9 PMID: 4345092
  39. Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.
    Proc Natl Acad Sci U S A. 1990 Feb;87(4):1426-30 PMID: 1689485
  40. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).
    Annu Rev Biochem. 1994;63:601-37 PMID: 7979249
  41. Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase.
    Protein Sci. 1995 Apr;4(4):756-64 PMID: 7613473
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.16.4617
Published
1998-08-17
Pages
4617-25
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170791
Subset
IM
Grants
NHLBI NIH HHS · R37 HL063762 · United States
NHLBI NIH HHS · HL20948 · United States
External Links
PubMed source DOI: 10.1093/emboj/17.16.4617 PMC Full Text View journal details
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