CELLULAR UPTAKE OF SAPOSIN (SAP) PRECURSOR AND LYSOSOMAL DELIVERY BY THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP)

Sphingolipid activator proteins SAP-A, -B, -C and -D (also called sapo sins) 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 recog nized by the mannose-6-phosphate (M-6-P) receptor and shuttled directl y from the secretory pathway to the lysosome, a substantial fraction o f newly synthesized precursor is secreted from the cell where it may p articipate in sphingolipid transport and signaling events. Re-uptake o f the secreted precursor is mediated by high-affinity cell surface rec eptors that are apparently distinct from the M-6-P receptor. We found that the low density lipoprotein receptor-related protein (LRP), a mul tifunctional endocytic receptor that is expressed on most cells, can m ediate cellular uptake and lysosomal delivery of SAP precursor. Additi onal in vivo experiments in mice revealed that the mannose receptor sy stem 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 mann ose receptor and LRP.