Sandhoff K, Klein A
Institut für Organische Chemie und Biochemie, Universität Bonn, Germany.
FEBS Lett. 1994 Jun 6;346(1):103-7. doi: 10.1016/0014-5793(94)00282-7.
Glycosphingolipids (GSL) are components of the outer leaflet of the plasma membrane (PM) of vertebrate tissues. Our current knowledge of GSL metabolism and their intracellular traffic has been derived from metabolic studies but the exact mechanisms by which GSLs are transported from sites of synthesis (endoplasmic reticulum and Golgi) to the sites of residence (PM) and degradation (lysosomes) have not been clearly defined. It is now established that components of the PM reach the lysosomal compartment mainly by endocytic membrane flow. According to a new model, GSLs derived from the PM are thought to end up in intra-endosomal vesicles which could be delivered, by successive processes of membrane fission and fusion, along the endocytic pathway directly into the lumen of the lysosomes. Here the GSLs are degraded in a step-wise manner by exohydrolases. However, the catabolism of membrane-bound GSLs with short hydrophilic head groups needs the assistance of sphingolipid activator proteins (SAPs), which lift the GSLs from the plane of the membrane and present them for degradation to the lysosomal exohydrolases, which are usually water-soluble. The inherited deficiency of one of these enzymes or SAPs causes the lysosomal storage of their respective GSL substrates. In the case of the simultaneous deficiency of all 4 different SAPs the storage of all GSLs with short hydrophilic head groups occurs within multivesicular bodies and/or intra-lysosomal vesicles.
糖鞘脂（GSL）是脊椎动物组织质膜（PM）外小叶的组成成分。我们目前对GSL代谢及其细胞内运输的了解来自代谢研究，但GSL从合成部位（内质网和高尔基体）运输到驻留部位（质膜）和降解部位（溶酶体）的确切机制尚未明确界定。现已确定，质膜成分主要通过内吞膜流到达溶酶体区室。根据一个新模型，源自质膜的GSL被认为最终进入内体小泡，这些小泡可通过膜分裂和融合的连续过程，沿着内吞途径直接递送至溶酶体腔。在这里，GSL被外切水解酶逐步降解。然而，具有短亲水头基团的膜结合GSL的分解代谢需要鞘脂激活蛋白（SAP）的协助，这些蛋白将GSL从膜平面上提起来，使其能够被通常为水溶性的溶酶体外切水解酶降解。这些酶或SAP中任何一种的遗传性缺陷都会导致其各自GSL底物在溶酶体中蓄积。在所有4种不同SAP同时缺乏的情况下，所有具有短亲水头基团的GSL都会蓄积在多泡体和/或溶酶体内小泡中。
