Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genet. 2022 Mar 16;18(3):e1010128. doi: 10.1371/journal.pgen.1010128. eCollection 2022 Mar.
Tissue homeostasis requires a delicate balance between stem cell self-renewal, proliferation, and differentiation. Essential to this process is glycosylation, with both intra-and extra-cellular glycosylation being required for stem cell homeostasis. However, it remains unknown how intracellular glycosylation, O-GlcNAcylation, interfaces with cellular components of the extracellular glycosylation machinery, like the cytosolic N-glycanase NGLY1. In this study, we utilize the Drosophila gut and uncover a pathway in which O-GlcNAcylation cooperates with the NGLY1 homologue PNG1 to regulate proliferation in intestinal stem cells (ISCs) and apoptosis in differentiated enterocytes. Further, the CncC antioxidant signaling pathway and ENGase, an enzyme involved in the processing of free oligosaccharides in the cytosol, interact with O-GlcNAc and PNG1 through regulation of protein aggregates to contribute to gut maintenance. These findings reveal a complex coordinated regulation between O-GlcNAcylation and the cytosolic glycanase PNG1 critical to balancing proliferation and apoptosis to maintain gut homeostasis.
组织稳态需要干细胞自我更新、增殖和分化之间的微妙平衡。糖基化对于这个过程至关重要，细胞内和细胞外的糖基化对于干细胞稳态都是必需的。然而，细胞内糖基化 O-连接糖基化如何与细胞外糖基化机制的细胞成分相互作用，例如细胞质 N-糖基酶 NGLY1，目前仍不清楚。在这项研究中，我们利用果蝇肠道揭示了一条途径，其中 O-连接糖基化与 NGLY1 同源物 PNG1 合作，调节肠道干细胞 (ISCs) 的增殖和分化的肠细胞的凋亡。此外，CncC 抗氧化信号通路和 ENGase（一种参与细胞质中游离寡糖加工的酶）通过调节蛋白质聚集体与 O-GlcNAc 和 PNG1 相互作用，有助于肠道维持。这些发现揭示了 O-连接糖基化和细胞质糖基酶 PNG1 之间复杂的协调调节，对于平衡增殖和凋亡以维持肠道稳态至关重要。
