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

作者：Stephanie Zimmermann, Lennart Pfannkuch, Munir A. Al‐Zeer, Sina Bartfeld, Manuel Koch, Jianping Liu, Cindy Rechner, Meike Soerensen, Olga Sokolova, Alla Zamyatina, Paul Kosma, André P. Mäurer, Frithjof Glowinski, Klaus‐Peter Pleißner, Monika Schmid, Volker Brinkmann, Alexander Karlas, Michael Naumann, Marion Rother, Nikolaus Machuy, Thomas F. Meyer · 发表于：Cell Reports · 年份：2017 · DOI：10.1016/j.celrep.2017.08.039 · 被引用次数：192 · 研究领域：Helicobacter pylori-related gastroenterology studies、Mycobacterium research and diagnosis、Immune Cell Function and Interaction

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.