Helicobacter pylori regulates TIFA turnover in gastric epithelial cells.

The human pathogen Helicobacter pylori induces a strong inflammatory response in gastric mucosa manifested by the recruitment of neutrophils and macrophages to the places of infection, and by changes in epithelial integrity and function. At the molecular level, this innate immune response is essentially dependent on the activation of NF-?B transcription factors regulating the expression of chemotactic factors, e.g., IL-8. Recently, it has been demonstrated that the NF-?B signaling pathway is triggered by the bacterial heptose metabolites, which activate the host ALPK1-TIFA axis. TIFA has been suggested to promote oligomerization and activity of the E3 ubiquitin ligase TRAF6, which further stimulates TAK1-IKK signaling. Here, we demonstrate that ALPK1-dependent TIFA activation in H. pylori-infected gastric epithelial cells is followed in time by a decline in TIFA levels, and that this process is impeded by inhibitors of the proteasomal and lysosomal degradation. According to our data, TRAF2, TRAF6, TAK1 or NEMO are not required for TIFA degradation. Additionally, H. pylori promotes the interaction of TIFA with free polyubiquitin as well as with optineurin, TAX1BP1 and LAMP1, which are known protein adaptors involved in intracellular trafficking to lysosomes.

Automated summary

Helicobacter pylori infection induces a strong inflammatory response in gastric mucosa and alters epithelial integrity and function. The activation of NF-κB transcription factors, specifically by the bacterial heptose metabolites, triggers this innate immune response. Our study reveals that the activation of ALPK1-dependent TIFA in H. pylori-infected gastric epithelial cells is followed by TIFA degradation, which is inhibited by proteasomal and lysosomal inhibitors. TRAF2, TRAF6, TAK1, or NEMO are not involved in TIFA degradation, and H. pylori promotes the interaction of TIFA with protein adaptors involved in lysosomal trafficking.