Protein O-glucosylation is a crucial form of O-glycosylation, which involves glucose (Glc) addition to a serine residue within a consensus sequence of epidermal growth factor epidermal growth factor (EGF)-like repeats found in several proteins, including Notch. Glc provides stability to EGF-like repeats, is required for S2 cleavage of Notch, and serves to regulate the trafficking of Notch, crumbs2, and Eyes shut proteins to the cell surface. Genetic and biochemical studies have shown a link between aberrant protein O-glucosylation and human diseases. The main players of protein O-glucosylation, protein O-glucosyltransferases (POGLUTs), use uridine diphosphate (UDP)-Glc as a substrate to modify EGF repeats and reside in the endoplasmic reticulum via C-terminal KDEL-like signals. In addition to O-glucosylation activity, POGLUTs can also perform protein O-xylosylation function, i.e., adding xylose (Xyl) from UDP-Xyl; however, both activities rely on residues of EGF repeats, active-site conformations of POGLUTs and sugar substrate concentrations in the ER. Impaired expression of POGLUTs has been associated with initiation and progression of human diseases such as limb-girdle muscular dystrophy, Dowling–Degos disease 4, acute myeloid leukemia, and hepatocytes and pancreatic dysfunction. POGLUTs have been found to alter the expression of cyclin-dependent kinase inhibitors (CDKIs), by affecting Notch or transforming growth factor-β1 signaling, and cause cell proliferation inhibition or induction depending on the particular cell types, which characterizes POGLUT’s cell-dependent dual role. Except for a few downstream elements, the precise mechanisms whereby aberrant protein O-glucosylation causes diseases are largely unknown, leaving behind many questions that need to be addressed. This systemic review comprehensively covers literature to understand the O-glucosyltransferases with a focus on POGLUT1 structure and function, and their role in health and diseases. Moreover, this study also raises unanswered issues for future research in cancer biology, cell communications, muscular diseases, etc.

蛋白质O-糖基化是O-糖基化的一种重要形式，它涉及将葡萄糖 (Glc) 添加到表皮生长因子表皮生长因子 (EGF) 样重复序列的共有序列中的丝氨酸残基，这些序列存在于包括 Notch 在内的多种蛋白质中。Glc 为 EGF 样重复序列提供稳定性，是 Notch 的 S2 切割所必需的，并用于调节 Notch、crumbs2 和 Eyes shut 蛋白向细胞表面的运输。遗传和生化研究表明异常的蛋白质O-糖基化与人类疾病之间存在联系。蛋白O-糖基化的主要参与者，蛋白O-葡萄糖基转移酶 (POGLUT)，使用尿苷二磷酸 (UDP)-Glc 作为底物来修饰 EGF 重复序列，并通过 C 末端 KDEL 样信号驻留在内质网中。除了O-糖基化活性外，POGLUT 还可以进行蛋白O-木糖基化功能，即从UDP-Xyl添加木糖(Xyl)；然而，这两种活动都依赖于 EGF 重复序列的残基、POGLUT 的活性位点构象和 ER 中的糖底物浓度。POGLUT 表达受损与人类疾病的发生和发展有关，例如肢带型肌营养不良症、Dowling–Degos 病 4、急性髓性白血病以及肝细胞和胰腺功能障碍。已发现 POGLUT 通过影响 Notch 或转化生长因子-β1 信号转导改变细胞周期蛋白依赖性激酶抑制剂 (CDKI) 的表达，并根据特定细胞类型引起细胞增殖抑制或诱导，这表征了 POGLUT 的细胞依赖性双重作用角色。除了少数下游元件外，异常蛋白O的精确机制-糖基化引起的疾病在很大程度上是未知的，留下了许多需要解决的问题。这篇系统综述全面涵盖了了解O -葡萄糖基转移酶的文献，重点是 POGLUT1 的结构和功能，以及它们在健康和疾病中的作用。此外，这项研究还为未来在癌症生物学、细胞通讯、肌肉疾病等方面的研究提出了未解决的问题。