Cell Reports
Volume 20, Issue 10, 5 September 2017, Pages 2384-2395
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Article
ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System

https://doi.org/10.1016/j.celrep.2017.08.039Get rights and content
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Highlights

  • Genome-wide RNAi screen identifies key innate immune pathway induced by H. pylori

  • Release of LPS metabolite HBP via H. pylori’s type IV secretion activates NF-κB

  • The ALPK1-TIFA axis constitutes a core pathogen-specific pattern recognition system

Summary

Activation of transcription factor NF-κB 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-1β- and TNF-α-dependent NF-κB 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-β-D-manno-heptose 1,7-bisphosphate (βHBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-κB activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-κB 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-κB 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.

Keywords

NF-κB signaling
genome-wide RNAi screen
inflammation
pathogen-associated molecular pattern
PAMP
D-glycero-β-D-manno-heptose 1,7-bisphosphate
HBP

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