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

Chenxi Xu; Xing Liu; Huangyuan Zha; Sijia Fan; Dawei Zhang; Shan Li; Wuhan Xiao

doi:10.1371/journal.ppat.1007259

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

PLoS Pathog. 2018 Aug 20;14(8):e1007259. doi: 10.1371/journal.ppat.1007259. eCollection 2018 Aug.

Authors

Chenxi Xu^{1

2}, Xing Liu¹, Huangyuan Zha¹, Sijia Fan¹, Dawei Zhang¹, Shan Li^{3

4}, Wuhan Xiao^{1

5}

Affiliations

¹ State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, P. R. China.
² University of Chinese Academy of Sciences, Beijing, P. R. China.
³ Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, P. R. China.
⁴ Biomedical Center, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, P. R. China.
⁵ The Key laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, P. R. China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acylation
Animals
Arginine / metabolism
Carbohydrate Metabolism* / genetics
Cells, Cultured
Enteropathogenic Escherichia coli* / genetics
Enteropathogenic Escherichia coli* / metabolism
Escherichia coli Proteins / genetics
Escherichia coli Proteins / metabolism
Escherichia coli Proteins / physiology*
Glucose / metabolism*
Glycosylation
HCT116 Cells
HEK293 Cells
HeLa Cells
Host-Pathogen Interactions / genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Male
Mice
Mice, Inbred C57BL
N-Acetylglucosaminyltransferases / metabolism
Virulence Factors / genetics
Virulence Factors / metabolism
Virulence Factors / physiology*

Substances

Escherichia coli Proteins
Hypoxia-Inducible Factor 1, alpha Subunit
NleB protein, E coli
Virulence Factors
Arginine
N-Acetylglucosaminyltransferases
Glucose

Grants and funding

WX was supported by The Strategic Priority Research Program of the Chinese Academy of Sciences [XDA08010208.] and NSFC [91631102, 31830101 and 31721005]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.