ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System

  • Cell Rep. 2017 Sep 5;20(10):2384-2395. doi: 10.1016/j.celrep.2017.08.039.
Stephanie Zimmermann  1 ,  Lennart Pfannkuch  1 ,  Munir A Al-Zeer  1 ,  Sina Bartfeld  2 ,  Manuel Koch  1 ,  Jianping Liu  1 ,  Cindy Rechner  1 ,  Meike Soerensen  1 ,  Olga Sokolova  3 ,  Alla Zamyatina  4 ,  Paul Kosma  4 ,  André P Mäurer  1 ,  Frithjof Glowinski  1 ,  Klaus-Peter Pleissner  1 ,  Monika Schmid  1 ,  Volker Brinkmann  1 ,  Alexander Karlas  1 ,  Michael Naumann  3 ,  Marion Rother  5 ,  Nikolaus Machuy  1 ,  Thomas F Meyer  6
Affiliations
  • 1. Department of Molecular Biology, Max-Planck Institute for Infection Biology, 10117 Berlin, Germany.
  • 2. Department of Molecular Biology, Max-Planck Institute for Infection Biology, 10117 Berlin, Germany; Research Center for Infectious Diseases, ZINF, Institute for Molecular Infection Biology, IMIB, University of Würzburg, 97080 Würzburg, Germany.
  • 3. Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.
  • 4. Department of Chemistry, University of Natural Resources and Life Sciences-Vienna, 1190 Vienna, Austria.
  • 5. Steinbeis Innovation, Center for Systems Biomedicine, 14612 Berlin-Falkensee, Germany.
  • 6. Department of Molecular Biology, Max-Planck Institute for Infection Biology, 10117 Berlin, Germany; Steinbeis Innovation, Center for Systems Biomedicine, 14612 Berlin-Falkensee, Germany. Electronic address: [email protected].
PMID: 28877472 DOI: 10.1016/j.celrep.2017.08.039
Abstract

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