Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Research Campus, Martinistrasse 52, 20246 Hamburg, Germany.
Eur J Cell Biol. 2010 Jan;89(1):117-23. doi: 10.1016/j.ejcb.2009.10.008. Epub 2009 Nov 28.
Lysosomal hydrolases catalyze the degradation of a variety of macromolecules including proteins, carbohydrates, nucleic acids and lipids. The biogenesis of lysosomes or lysosome-related organelles requires a continuous substitution of soluble acid hydrolases and lysosomal membrane proteins. The targeting of lysosomal hydrolases depends on mannose 6-phosphate residues (M6P) that are recognized by specific receptors mediating their transport to an endosomal/prelysosomal compartment. The key role in the formation of M6P residues plays the GlcNAc-1-phosphotransferase localized in the Golgi apparatus. Two genes have been identified recently encoding the type III alpha/beta-subunit precursor membrane protein and the soluble gamma-subunit of GlcNAc-1-phosphotransferase. Mutations in these genes result in two severe diseases, mucolipidosis type II (MLII) and III (MLIII), biochemically characterized by the missorting of multiple lysosomal hydrolases due to impaired formation of the M6P recognition marker, and general lysosomal dysfunction. This review gives an update on structural properties, localization and functions of the GlcNAc-1-phosphotransferase subunits and improvements of pre- and postnatal diagnosis of ML patients. Further, the generation of recombinant single-chain antibody fragments against M6P residues and of new mouse models of MLII and MLIII will have considerable impact to provide deeper insight into the cell biology of lysosomal dysfunctions and the pathomechanisms underlying these lysosomal disorders.
溶酶体水解酶催化多种大分子的降解，包括蛋白质、碳水化合物、核酸和脂质。溶酶体或溶酶体相关细胞器的生物发生需要不断替代可溶性酸性水解酶和溶酶体膜蛋白。溶酶体水解酶的靶向依赖于甘露糖 6-磷酸残基（M6P），这些残基被特异性受体识别，介导其运输到内体/溶酶体隔室。GlcNAc-1-磷酸转移酶在 M6P 残基的形成中起着关键作用，该酶定位于高尔基体。最近已经鉴定出两个基因，分别编码 III 型 α/β-亚基前膜蛋白和 GlcNAc-1-磷酸转移酶的可溶性 γ-亚基。这些基因的突变导致两种严重疾病，粘脂病 II 型（MLII）和 III 型（MLIII），其生化特征是由于 M6P 识别标记形成受损，导致多种溶酶体水解酶的错误分拣，以及一般溶酶体功能障碍。这篇综述介绍了 GlcNAc-1-磷酸转移酶亚基的结构特性、定位和功能，以及 ML 患者的产前和产后诊断的改进。此外，针对 M6P 残基的重组单链抗体片段和 MLII 和 MLIII 的新型小鼠模型的产生将对深入了解溶酶体功能障碍的细胞生物学和这些溶酶体疾病的发病机制产生重大影响。
