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

Thomas Hiesberger, Silke Hüttler, Astrid Rohlmann, Wolfgang Schneider, Konrad Sandhoff, Joachim Herz

Research output: Contribution to journalArticle

67 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4617-4625
Number of pages9
JournalEMBO Journal
Volume17
Issue number16
DOIs
Publication statusPublished - Aug 17 1998

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Keywords

  • Endocytosis
  • Lipoprotein receptor-related protein
  • Mannose-6-phosphate
  • Saposin
  • Sphingolipid

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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