Membrane lipids and their degradation compounds control GM2 catabolism at intralysosomal luminal vesicles
Membrane lipids and their degradation compounds control GM2 catabolism at intralysosomal luminal vesicles
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DOI：
10.1194/jlr.m092551
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发表时间：
2019-06-01
影响因子：
6.5
通讯作者：
Sandhoff, Konrad
中科院分区：
文献类型：
--
作者：
Anheuser, Susi;Breiden, Bernadette;Sandhoff, Konrad
神经节苷脂 GM2 的分解代谢依赖于三种基因产物。这些基因中任何一个的突变都会导致不同类型的 GM2 神经节苷脂贮积症（Tay-Sachs 病、Sandhoff 病以及 GM2 神经节苷脂贮积症的 B1 和 AB 变体），其中 GM2 是主要的溶酶体储存化合物。 GM2 也是溶酶体贮积病（例如 A-C 型尼曼匹克病）中的次级贮积化合物，其中 A 型主要贮藏 SM，B 型和 C 型主要贮藏胆固醇。携带 GM2 的脂质体表面的 GM2 分解代谢重建表明，将脂质（例如胆固醇、SM、鞘氨醇和二氢鞘氨醇）掺入到 GM2 携带膜中，可在 GM2 激活蛋白的辅助下抑制 β-己糖胺酶 A 水解 GM2，而阴离子脂质、神经酰胺、脂肪酸、 溶血磷脂酰胆碱和二酰甘油刺激 GM2 分解代谢。相比之下，合成的水溶性底物4-甲基伞形基-6-磺基-2-乙酰酰胺-2-脱氧--d-吡喃葡萄糖苷的水解既不受神经酰胺或SM等膜脂的显着影响，也不受作为脂质体添加的双(单酰基甘油)磷酸盐等阴离子脂质的刺激， 洗涤剂胶束或脂质聚集体。此外，水解抑制脂质还对GM2激活蛋白对膜结合脂质的溶解和动员有抑制作用，而刺激脂质则增强脂质动员。
The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. GM2 is also a secondary storage compound in lysosomal storage diseases such as Niemann-Pick disease types A-C, with primary storage of SM in type A and cholesterol in types B and C, respectively. The reconstitution of GM2 catabolism at liposomal surfaces carrying GM2 revealed that incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by -hexosaminidase A assisted by GM2 activator protein, while anionic lipids, ceramide, fatty acids, lysophosphatidylcholine, and diacylglycerol stimulate GM2 catabolism. In contrast, the hydrolysis of the synthetic, water-soluble substrate 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy--d-glucopyranoside was neither significantly affected by membrane lipids such as ceramide or SM nor stimulated by anionic lipids such as bis(monoacylglycero)phosphate added as liposomes, detergent micelles, or lipid aggregates. Moreover, hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein, while the stimulating lipids enhanced lipid mobilization.