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

Date Published: August 20, 2018

Publisher: Public Library of Science

Author(s): Chenxi Xu, Xing Liu, Huangyuan Zha, Sijia Fan, Dawei Zhang, Shan Li, Wuhan Xiao, Brian K. Coombes.

http://doi.org/10.1371/journal.ppat.1007259

Abstract

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.

Partial Text

Over the past decade, it has become clear that pathogens play an important role in host metabolism, but the mechanisms by which they affect host metabolism remain poorly defined [1–10]. Although pathogenic organisms likely rely on effectors to communicate with their host, the identity and function of pathogen-encoded effectors remain largely unknown [2,8,9]. Identifying pathogen effectors that affect host metabolism and defining the pathways that effectors use to enact their changes to host metabolism can help us better understand the relationship between pathogen infection and host physiology, as well as provide insights into the mechanisms underlying human diseases related to metabolic disturbance, such as obesity and type 2 diabetes (T2DM).

Accumulating evidence has revealed that pathogens affect energy homeostasis, glucose metabolism, and metabolic inflammation, but the causal link between pathogen infection and host metabolism remains to be fully understood [10,55,56]. In this study, our finding that bacterial NleB, a virulence protein (effector) delivered by the T3SS in gut A/E pathogens such as EPEC or C. rodentium, modulates host glucose metabolism by GlcNAcylating arginine residues in HIF-1α [13] provides a causal link between pathogen infection and host glucose metabolism; furthermore, this finding could open new avenues for exploring the underlying causes by which pathogen infection affects host metabolism. Given that the regulation of host glucose metabolism is complicated and that HIF-1α mainly participates in glucose metabolism under hypoxia [20], future studies determining how pathogens modulate host glucose metabolism beyond HIF-1 signaling would be of great interest.

 

Source:

http://doi.org/10.1371/journal.ppat.1007259