O-GlcNAcase Expression is Sensitive to Changes in O-GlcNAc Homeostasis.
O-GlcNAcase Expression is Sensitive to Changes in O-GlcNAc Homeostasis.
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DOI：
10.3389/fendo.2014.00206
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发表时间：
2014
影响因子：
5.2
通讯作者：
Slawson C
中科院分区：
文献类型：
--
作者：
Zhang Z;Tan EP;VandenHull NJ;Peterson KR;Slawson C
O-连接N-乙酰葡糖胺（O-GlcNAc）是一种翻译后修饰，涉及单个β-N-乙酰葡糖胺部分与细胞核和细胞质蛋白中的丝氨酸或苏氨酸残基的连接。细胞O-GlcNAc水平由两种酶调节：O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA），它们分别添加和去除修饰。O-GlcNAc的水平可以响应于细胞外环境中的波动而迅速变化;然而，O-GlcNAc化在刺激去除后迅速返回到基线水平。这一过程被称为O-GlcNAc稳态似乎是至关重要的许多细胞功能的调节，包括细胞周期的进展，应激反应，和基因转录。O-GlcNAc稳态的破坏被认为会导致疾病的发展，例如癌症、糖尿病和阿尔茨海默病。O-GlcNAc稳态与OGT和OGA的表达相关。我们推断O-GlcNAc水平的改变影响OGA和OGT转录。我们用Thiamet-G（TMG，一种OGA抑制剂）处理几种人细胞系以增加总体O-GlcNAc水平，导致OGT蛋白表达降低和OGA蛋白表达增加。TMG处理的OGT转录水平略有下降，但OGA转录水平显着增加。用蛋白质翻译抑制剂放线菌酮预处理细胞在TMG存在下不能稳定OGT或OGA蛋白表达;当用RNA转录抑制剂放线菌素D处理细胞时，TMG也不能稳定OGT和OGA mRNA水平。最后，我们进行了RNA聚合酶II染色质免疫沉淀在OGA启动子，并发现RNA Pol II占用在转录起始位点较低后，长期TMG治疗。总之，这些数据表明OGA转录对O-GlcNAc稳态的变化敏感，并且可能受O-GlcNAc调节。
O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification involving an attachment of a single β-N-acetylglucosamine moiety to serine or threonine residues in nuclear and cytoplasmic proteins. Cellular O-GlcNAc levels are regulated by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add and remove the modification, respectively. The levels of O-GlcNAc can rapidly change in response to fluctuations in the extracellular environment; however, O-GlcNAcylation returns to a baseline level quickly after stimulus removal. This process termed O-GlcNAc homeostasis appears to be critical to the regulation of many cellular functions including cell cycle progress, stress response, and gene transcription. Disruptions in O-GlcNAc homeostasis are proposed to lead to the development of diseases, such as cancer, diabetes, and Alzheimer’s disease. O-GlcNAc homeostasis is correlated with the expression of OGT and OGA. We reason that alterations in O-GlcNAc levels affect OGA and OGT transcription. We treated several human cell lines with Thiamet-G (TMG, an OGA inhibitor) to increase overall O-GlcNAc levels resulting in decreased OGT protein expression and increased OGA protein expression. OGT transcript levels slightly declined with TMG treatment, but OGA transcript levels were significantly increased. Pretreating cells with protein translation inhibitor cycloheximide did not stabilize OGT or OGA protein expression in the presence of TMG; nor did TMG stabilize OGT and OGA mRNA levels when cells were treated with RNA transcription inhibitor actinomycin D. Finally, we performed RNA Polymerase II chromatin immunoprecipitation at the OGA promoter and found that RNA Pol II occupancy at the transcription start site was lower after prolonged TMG treatment. Together, these data suggest that OGA transcription was sensitive to changes in O-GlcNAc homeostasis and was potentially regulated by O-GlcNAc.
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