State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China.
University of Chinese Academy of Sciences, Beijing, P. R. China.
PLoS Pathog. 2018 Aug 20;14(8):e1007259. doi: 10.1371/journal.ppat.1007259. eCollection 2018 Aug.
The essential role of pathogens in host metabolism is widely recognized, yet the mechanisms by which they affect host physiology remain to be fully defined. Here, we found that NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to possess N-acetylglucosamine (GlcNAc) transferase activity, GlcNAcylates HIF-1α, a master regulator of cellular O2 homeostasis. We determined that NleB-mediated GlcNAcylation at a conserved arginine 18 (Arg18) at the N-terminus of HIF-1α enhanced HIF-1α transcriptional activity, thereby inducing HIF-1α downstream gene expression to alter host glucose metabolism. The arginine transferase activity of NleB was required for its enhancement of HIF-1α transactivity and the subsequent effect on glucose metabolism in a mouse model of EPEC infection. In addition, HIF-1α acted as a mediator to transact NleB-mediated induction of glucose metabolism-associated gene expression under hypoxia. Thus, our results further show a causal link between pathogen infection and host glucose metabolism, and we propose a new mechanism by which this occurs.
病原体在宿主代谢中的重要作用已被广泛认可，但它们影响宿主生理学的机制仍有待完全确定。在这里，我们发现，肠致病性大肠杆菌（EPEC）III 型分泌系统效应物 NleB 具有 N-乙酰葡萄糖胺（GlcNAc）转移酶活性，已知该蛋白能使 HIF-1α发生 GlcNAc 化修饰，而后者是细胞 O2 稳态的主要调节因子。我们确定，NleB 介导的 HIF-1α N 端保守精氨酸 18（Arg18）的 GlcNAc 化修饰增强了 HIF-1α 的转录活性，从而诱导 HIF-1α 下游基因表达，改变宿主的葡萄糖代谢。NleB 的精氨酸转移酶活性是其增强 HIF-1α 转录活性以及随后在 EPEC 感染的小鼠模型中对葡萄糖代谢的影响所必需的。此外，在缺氧条件下，HIF-1α 作为一种介导物，可使 NleB 介导的葡萄糖代谢相关基因表达的诱导发生转导。因此，我们的研究结果进一步表明了病原体感染与宿主葡萄糖代谢之间的因果关系，并提出了这种关联发生的新机制。
