A pathogen-derived effector modulates host glucose metabolism by arginine GlcNAcylation of HIF-1α protein.

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.