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Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains

Shan Li1, Li Zhang, Qing Yao

  • 1College of Biological Sciences, China Agricultural University, Beijing 100094, China.

Nature
|August 20, 2013
PubMed

Insights

Enteropathogenic Escherichia coli uses NleB to inhibit host immune responses by modifying death domains, blocking crucial cell signaling pathways like NF-κB, apoptosis, and necroptosis. This bacterial mechanism, involving N-acetylglucosamine transferase activity, is vital for infection.

Area of Science:

  • Microbiology
  • Immunology
  • Molecular Biology

Background:

  • Tumor Necrosis Factor (TNF) signaling is critical for immune homeostasis, inflammation, and cell death.
  • TNF receptor (TNFR) family members, like TNFR1 and FAS, mediate these signals through death domains.
  • These domains interact with adaptor proteins such as TRADD and FADD to trigger downstream signaling.

Purpose of the Study:

  • To identify the mechanism by which enteropathogenic Escherichia coli (EPEC) inhibits host immune signaling.
  • To investigate the role of the EPEC type III secretion system effector NleB in modulating death receptor pathways.
  • To characterize the enzymatic activity of NleB and its impact on host cell death and inflammation.

Main Methods:

  • Biochemical assays to determine NleB's enzymatic activity.
  • Site-directed mutagenesis to identify key residues in NleB and target death domains.
  • Cell-based assays to assess NF-κB signaling, apoptosis, and necroptosis.
  • In vivo infection models to evaluate the role of NleB in bacterial colonization.

Main Results:

  • NleB possesses N-acetylglucosamine (GlcNAc) transferase activity, modifying a conserved arginine in death domains of proteins including TRADD, FADD, RIPK1, and TNFR1.
  • This GlcNAcylation inactivates death domains, preventing essential protein-protein interactions and the assembly of signaling complexes like the TNFR1 complex and DISC.
  • Disruption of TNF, NF-κB, apoptosis, and necroptosis signaling was observed in EPEC-infected cells.
  • NleB's GlcNAc transferase activity was essential for EPEC colonization in a mouse model.

Conclusions:

  • NleB from EPEC directly inhibits host TNFR and FAS signaling pathways through a novel post-translational modification (GlcNAcylation) of death domains.
  • This bacterial strategy effectively counteracts host immune responses, including inflammation and cell death.
  • The discovery of NleB's arginine GlcNAc transferase activity reveals a new mechanism of bacterial pathogenesis and an unappreciated form of protein modification.

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