2. Academic Validation
  3. ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System

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

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.

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