RT Journal Article
SR Electronic
T1 ALPK1 and TIFA dependent innate immune response triggered by the Helicobacter pylori type IV secretion system
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 139998
DO 10.1101/139998
A1 Stephanie Zimmermann
A1 Lennart Pfannkuch
A1 Munir A. Al-Zeer
A1 Sina Bartfeld
A1 Manuel Koch
A1 Jianping Liu
A1 Cindy Rechner
A1 Meike Soerensen
A1 Olga Sokolova
A1 Alla Zamyatina
A1 Paul Kosma
A1 André P. Mäurer
A1 Frithjof Glowinski
A1 Klaus-Peter Pleissner
A1 Monika Schmid
A1 Volker Brinkmann
A1 Michael Naumann
A1 Marion Rother
A1 Nikolaus Machuy
A1 Thomas F. Meyer
YR 2017
UL http://biorxiv.org/content/early/2017/05/19/139998.abstract
AB Activation of transcription factor NF-κB is a hallmark of infection with the gastric pathogen Helicobacter pylori and associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous hits 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 as well as TIFAsome formation depended on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as core of a novel 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.