Journal
CELL REPORTS
Volume 20, Issue 10, Pages 2384-2395Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.08.039
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Funding
- EU [LSHC-CT-2005-018704]
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Activation of transcription factor NF-kappa B is a hallmark of infection with the gastric pathogen Helicobacter pylori, associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous host factors involved in H. pylori-, but not IL-1 beta- and TNF-alpha-dependent NF-kappa B regulation. Pathway analysis including CRISPR/Cas9-knockout and recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry, and mutant H. pylori strains identified the H. pylori metabolite D-glycero-beta-D-manno-heptose 1,7-bisphosphate (bHBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-kappa B activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-kappa B activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as a core innate immune pathway. ALPK1-TIFA-mediated NF-kappa B activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogen's T4SS.
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