A20 undermines alternative NF-κB activity and expression of anti-apoptotic genes in Helicobacter pylori infection

Cell Mol Life Sci. 2022 Jan 28;79(2):102. doi: 10.1007/s00018-022-04139-y.

Abstract

A hallmark of infection by the pathogen Helicobacter pylori, which colonizes the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, underlying inflammation and cell survival. Here, we report that the classical NF-κB target gene product A20 contributes to the negative regulation of alternative NF-κB signaling in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesized A20 protein interacts with tumor necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) and thereby interferes with the association of TIFA with the NIK regulatory complex. We also show that alternative NF-κB activity contributes to the up-regulation of anti-apoptotic genes, such as baculoviral IAP repeat containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. Furthermore, the observed over-expression of RelB in human gastric biopsies with type B gastritis and RelB-dependent suppression of apoptotic cell death emphasize an important role of the alternative NF-κB pathway in H. pylori infection.

Keywords: ADP-heptose; LTα1β2; NIK; RelB; TIFA; p100.

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Baculoviral IAP Repeat-Containing 3 Protein / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism
  • Cell Line, Tumor
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / microbiology
  • Gastritis / genetics
  • Gastritis / metabolism
  • Gastritis / microbiology
  • Gene Expression
  • Gene Knockout Techniques
  • Helicobacter Infections / genetics
  • Helicobacter Infections / metabolism*
  • Helicobacter Infections / microbiology
  • Helicobacter pylori / physiology
  • Host-Pathogen Interactions
  • Humans
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction / genetics
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BCL2-related protein A1
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • RELA protein, human
  • RELB protein, human
  • Transcription Factor RelA
  • Transcription Factor RelB
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3