Issad Tarik, Pagesy Patrick
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France - INSERM, U1016, Paris, France.
Biol Aujourdhui. 2014;208(2):109-17. doi: 10.1051/jbio/2014015. Epub 2014 Sep 8.
O-GlcNAcylation corresponds to the addition of N-acetyl glucosamine (GlcNAc) on serine or threonine residues of cytosolic and nuclear proteins. This reversible post-translational modification regulates protein phosphorylation, sub-cellular localisation, stability and activity. Only two enzymes, OGT (O-linked N-acetyl-glucosaminyltransferase) and OGA (O-linked N-acetyl-β-D glucosaminidase), control the addition and removal of GlcNAc from more than a thousand of proteins. Alternative splicing generates different isoforms of OGT and OGA, and address these enzymes to different sub-cellular compartments (mitochondria, cytosol...), restraining their action to specific subsets of substrates. Moreover, interaction with adaptor proteins may also help address these enzymes to specific substrates. Alterations in protein O-GlcNAcylation have been observed in a number of important human diseases, such as Alzheimer, cancer and diabetes. A reciprocal relationship between Tau protein phosphorylation and O-GlcNAcylation has been observed, and decreased O-GlcNAcylation in the brain of patients with Alzheimer diseases may favour Tau aggregation, destabilisation of microtubules and neuronal alterations. Alterations in OGT/OGA expression levels, and in protein O-GlcNAcylation, have been described in different types of cancer, and much evidence indicates that O-GlcNAcylation may participate in abnormal proliferation and migration of cancer cells. O-GlcNAcylation of transcription factors and signalling effectors may also participate in defects observed in diabetes. Indeed, in situation of chronic hyperglycaemia, abnormal O-GlcNAcylation may have deleterious effect on insulin secretion and action, resulting in further impairment of glucose homeostasis. Therefore, O-GlcNAcylation appears to be a major regulator of cellular activities and may play an important part in different human diseases. However, because of the large spectrum of OGT and OGA substrates, targeting O-GlcNAc for treatment of these diseases will be a highly challenging task.
O-连接的N-乙酰葡糖胺化作用是指在胞质和核蛋白的丝氨酸或苏氨酸残基上添加N-乙酰葡糖胺（GlcNAc）。这种可逆的翻译后修饰调节蛋白质磷酸化、亚细胞定位、稳定性和活性。只有两种酶，即O-连接的N-乙酰葡糖胺基转移酶（OGT）和O-连接的N-乙酰-β-D-葡糖胺酶（OGA），控制着从一千多种蛋白质上添加和去除GlcNAc。可变剪接产生OGT和OGA的不同异构体，并将这些酶定位于不同的亚细胞区室（线粒体、细胞质等），将它们的作用限制在特定的底物子集上。此外，与衔接蛋白的相互作用也可能有助于将这些酶定位于特定的底物。在许多重要的人类疾病中，如阿尔茨海默病、癌症和糖尿病，都观察到了蛋白质O-连接的N-乙酰葡糖胺化作用的改变。已经观察到Tau蛋白磷酸化和O-连接的N-乙酰葡糖胺化作用之间存在相互关系，阿尔茨海默病患者大脑中O-连接的N-乙酰葡糖胺化作用降低可能有利于Tau聚集、微管不稳定和神经元改变。在不同类型的癌症中，已经描述了OGT/OGA表达水平和蛋白质O-连接N-乙酰葡糖胺化作用的改变，许多证据表明O-连接的N-乙酰葡糖胺化作用可能参与癌细胞的异常增殖和迁移。转录因子和信号效应器的O-连接的N-乙酰葡糖胺化作用也可能参与糖尿病中观察到的缺陷。事实上，在慢性高血糖的情况下，异常O-连接的N-乙酰葡糖胺化作用可能对胰岛素分泌和作用产生有害影响，导致葡萄糖稳态进一步受损。因此，O-连接的N-乙酰葡糖胺化作用似乎是细胞活动的主要调节因子，可能在不同的人类疾病中起重要作用。然而，由于OGT和OGA底物范围广泛，针对O-连接的N-乙酰葡糖胺治疗这些疾病将是一项极具挑战性的任务。
