https://ror.org/00q4vv597 Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, SAR of China.
https://ror.org/00q4vv597 Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, SAR of China
Life Sci Alliance. 2024 Nov 22;8(2). doi: 10.26508/lsa.202402941. Print 2025 Feb.
The plasma membrane has a complex organization that includes the polarized distribution of membrane proteins and lipids. Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are ubiquitously expressed in eukaryotes and represent a functionally diverse, extensively remodeled, ER-derived group of proteins critical for the organization and function of the plasma membrane. Little is known about how the transport of incompletely remodeled GPI-APs to the plasma membrane affects cell function. Here, we investigated how failure to remodel mannose 2 (Man2) of the GPI moiety impacted endocytic activity on the plasma membrane. We find that Man2 unremodeled GPI-APs increased membrane disorder and generated a stress response that triggered abnormal ubiquitin- and clathrin-dependent endocytosis. The resulting stress-induced endocytosis disrupted the trafficking repertoire of a subset of plasma membrane proteins, which were redirected, via the multivesicular body, to numerous small vacuoles for degradation. Our findings highlight the critical importance of GPI-AP Man2 remodeling for maintaining the integrity and homeostasis of the plasma membrane.
质膜具有复杂的组织，包括膜蛋白和脂质的极化分布。糖基磷脂酰肌醇锚定蛋白（GPI-APs）在真核生物中广泛表达，代表了一组功能多样、广泛重塑的内质网衍生蛋白，对质膜的组织和功能至关重要。关于不完全重塑的 GPI-AP 向质膜的运输如何影响细胞功能，目前知之甚少。在这里，我们研究了 GPI 部分的甘露糖 2（Man2）未能重塑如何影响质膜上的内吞作用。我们发现，未重塑的 GPI-APs 增加了膜无序性，并引发了一种应激反应，触发了异常的泛素和网格蛋白依赖性内吞作用。由此产生的应激诱导的内吞作用破坏了一部分质膜蛋白的运输库，这些蛋白通过多泡体被重新定向到许多用于降解的小空泡中。我们的研究结果强调了 GPI-AP Man2 重塑对于维持质膜完整性和体内平衡的至关重要性。
