Helicobacter pylori induces direct activation of the lymphotoxin beta receptor and non-canonical nuclear factor-kappa B signaling

Biochim Biophys Acta Mol Cell Res. 2018 Apr;1865(4):545-550. doi: 10.1016/j.bbamcr.2018.01.006. Epub 2018 Jan 9.

Abstract

The pathogen Helicobacter pylori, which infects half of the world's population, is a major risk factor for the development of gastric diseases including chronic gastritis and gastric cancer. Among H. pylori's virulence factors is the cytotoxin-associated gene pathogenicity island (cagPAI), which encodes for a type IV secretion system (T4SS). The T4SS induces fast canonical nuclear factor-kappa B (NF-κB) signaling, a major factor increasing inflammation, supressing apoptotic cell death and thereby promoting the development of neoplasia. However, H. pylori's capability to mediate fast non-canonical NF-κB signaling is unresolved, despite a contribution of non-canonical NF-κB signaling to gastric cancer has been suggested. We analyzed signaling elements within non-canonical NF-κB in response to H. pylori in epithelial cell lines by immunoprecipitation, immunoblot, electrophoretic mobility shift assay and RNA interference knockdown. In addition, tissue samples of H. pylori-infected patients were investigated by immunohistochemistry. Here, we provide evidence for a T4SS-dependent direct activation of non-canonical NF-κB signaling. We identified the lymphotoxin beta receptor (LTβR) to elicit the fast release of NF-κB inducing kinase (NIK) from the receptor complex leading to non-canonical NF-κB signaling. Further, NIK expression was increased in human biopsies of H. pylori-associated gastritis. Thus, NIK could represent a novel target to reduce Helicobacter pylori-induced gastric inflammation and pathology.

Keywords: Gastritis; Inflammation; NIK; Type IV secretion system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Bacterial / metabolism
  • Bacterial Proteins / metabolism
  • Bacterial Secretion Systems
  • HeLa Cells
  • Helicobacter pylori / metabolism*
  • Humans
  • Lymphotoxin beta Receptor / metabolism*
  • Middle Aged
  • Models, Biological
  • Mucous Membrane / metabolism
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • Stomach / pathology
  • Young Adult

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Bacterial Secretion Systems
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • cagA protein, Helicobacter pylori
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase