Hiesberger T, Hüttler S, Rohlmann A, Schneider W, Sandhoff K, Herz J
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA.
EMBO J. 1998 Aug 17;17(16):4617-25. doi: 10.1093/emboj/17.16.4617.
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.
鞘脂激活蛋白SAP - A、- B、- C和- D（也称为鞘aposins）由一种73 kDa前体经蛋白水解加工产生，作为参与糖鞘脂代谢的溶酶体酶的必需激活剂发挥作用。尽管SAP前体可被甘露糖-6-磷酸（M - 6 - P）受体识别，并直接从分泌途径转运至溶酶体，但新合成的前体中有相当一部分从细胞分泌出来，在细胞外它可能参与鞘脂转运和信号转导事件。分泌的前体的再摄取由高亲和力细胞表面受体介导，这些受体显然不同于M - 6 - P受体。我们发现，低密度脂蛋白受体相关蛋白（LRP），一种在大多数细胞上表达的多功能内吞受体，可介导SAP前体的细胞摄取和溶酶体递送。在小鼠体内进行的其他实验表明，巨噬细胞上的甘露糖受体系统也参与前体的内化。我们得出结论，SAP前体通过至少三种独立的受体机制进入细胞，包括M - 6 - P受体、甘露糖受体和LRP。
