Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Department of Chemistry, Osaka University, Toyonaka, Japan.
EMBO Rep. 2022 Jul 5;23(7):e54352. doi: 10.15252/embr.202154352. Epub 2022 May 23.
Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor many proteins (GPI-APs) on the cell surface. The core glycan of GPI precursor has three mannoses, which in mammals, are all modified by ethanolamine-phosphate (EthN-P). It is postulated that EthN-P on the third mannose (EthN-P-Man3) is the bridge between GPI and the protein and the second (EthN-P-Man2) is removed after GPI-protein attachment. However, EthN-P-Man2 may not be always transient, as mutations of PIGG, the enzyme that transfers EthN-P to Man2, result in inherited GPI deficiencies (IGDs), characterized by neuronal dysfunctions. Here, we show that EthN-P on Man2 is the preferential bridge in some GPI-APs, among them, the Ect-5'-nucleotidase and Netrin G2. We find that CD59, a GPI-AP, is attached via EthN-P-Man2 both in PIGB-knockout cells, in which GPI lacks Man3, and with a small fraction in wild-type cells. Our findings modify the current view of GPI anchoring and provide a mechanistic basis for IGDs caused by PIGG mutations.
糖基磷脂酰肌醇（GPI）是一种糖脂，可将许多蛋白质（GPI-AP）锚定在细胞表面。GPI 前体的核心聚糖有三个甘露糖，在哺乳动物中，全部被乙醇胺磷酸（EthN-P）修饰。据推测，GPI 与蛋白质之间的连接桥是在第三个甘露糖（EthN-P-Man3）上，而第二个（EthN-P-Man2）在 GPI-蛋白附着后被去除。然而，EthN-P-Man2 可能并不总是瞬时的，因为将 EthN-P 转移到 Man2 的酶 PIGG 的突变会导致遗传性 GPI 缺乏症（IGD），其特征是神经元功能障碍。在这里，我们表明，在一些 GPI-AP 中，EthN-P-Man2 是优先的连接桥，其中包括外核苷酸酶和 Netrin G2。我们发现，CD59 是一种 GPI-AP，它通过 EthN-P-Man2 连接在 PIGB 敲除细胞中，在这些细胞中，GPI 缺乏 Man3，而在野生型细胞中只有一小部分。我们的发现改变了 GPI 锚定的当前观点，并为 PIGG 突变引起的 IGD 提供了机制基础。
