Rescue of Glycosylphosphatidylinositol-Anchored Protein Biosynthesis Using Synthetic Glycosylphosphatidylinositol Oligosaccharides,ACS Chemical Biology

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Rescue of Glycosylphosphatidylinositol-Anchored Protein Biosynthesis Using Synthetic Glycosylphosphatidylinositol Oligosaccharides
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-10-07 , DOI: 10.1021/acschembio.1c00465
Paula A Guerrero _{1,

2} , Yoshiko Murakami _{3,

4} , Ankita Malik _{1,

2} , Peter H Seeberger _{1,

2} , Taroh Kinoshita _{3,

4} , Daniel Varón Silva _{1,

2}

Affiliation

The attachment of proteins to the cell membrane using a glycosylphosphatidylinositol (GPI) anchor is a ubiquitous process in eukaryotic cells. Deficiencies in the biosynthesis of GPIs and the concomitant production of GPI-anchored proteins lead to a series of rare and complicated disorders associated with inherited GPI deficiencies (IGDs) in humans. Currently, there is no treatment for patients suffering from IGDs. Here, we report the design, synthesis, and use of GPI fragments to rescue the biosynthesis of GPI-anchored proteins (GPI-APs) caused by mutation in genes involved in the assembly of GPI-glycolipids in cells. We demonstrated that the synthetic fragments GlcNAc-PI (1), Man-GlcN-PI (5), and GlcN-PI with two (3) and three lipid chains (4) rescue the deletion of the GPI biosynthesis in cells devoid of the PIGA, PIGL, and PIGW genes in vitro. The compounds allowed for concentration-dependent recovery of GPI biosynthesis and were highly active on the cytoplasmic face of the endoplasmic reticulum membrane. These synthetic molecules are leads for the development of treatments for IGDs and tools to study GPI-AP biosynthesis.

中文翻译：

使用合成的糖基磷脂酰肌醇寡糖拯救糖基磷脂酰肌醇锚定蛋白的生物合成

使用糖基磷脂酰肌醇 (GPI) 锚将蛋白质附着到细胞膜上是真核细胞中普遍存在的过程。GPI 生物合成的缺陷和伴随产生的 GPI 锚定蛋白导致一系列与人类遗传性 GPI 缺陷 (IGD) 相关的罕见且复杂的疾病。目前，没有针对患有 IGD 的患者的治疗方法。在这里，我们报告了 GPI 片段的设计、合成和使用，以挽救由参与细胞中 GPI-糖脂组装的基因突变引起的 GPI 锚定蛋白 (GPI-APs) 的生物合成。我们证明了合成片段 GlcNAc-PI ( 1 )、Man-GlcN-PI ( 5 ) 和具有两条 ( 3 ) 和三条脂质链 ( 4 ) 的GlcN-PI) 在体外挽救缺乏 PIGA、PIGL 和 PIGW 基因的细胞中 GPI 生物合成的缺失。这些化合物允许 GPI 生物合成的浓度依赖性恢复，并且在内质网膜的细胞质面上具有高度活性。这些合成分子是开发 IGD 治疗方法和研究 GPI-AP 生物合成的工具的先导。

更新日期：2021-11-19

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