5 years ago

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
Klaus-Peter Pleissner, Manuel Koch, Olga Sokolova, Meike Soerensen, Marion Rother, Lennart Pfannkuch, Monika Schmid, André P. Mäurer, Munir A. Al-Zeer, Nikolaus Machuy, Volker Brinkmann, Jianping Liu, Sina Bartfeld, Stephanie Zimmermann, Thomas F. Meyer, Alexander Karlas, Alla Zamyatina, Cindy Rechner, Frithjof Glowinski, Michael Naumann, Paul Kosma


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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31146-4

DOI: 10.1016/j.celrep.2017.08.039

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