ALPK1 And TIFA Dependent Innate Immune Response Triggered By The Helicobacter Pylori Type IV Secretion System

Zimmermann, S.; Pfannkuch, L.; Al-Zeer, M.; Bartfeld, S.; Koch, M.; Liu, J.; Rechner, C.; Soerensen, M.; Sokolova, O.; Zamyatina, A.; Kosma, P.; Maeurer, A. P.; Glowinski, F.; Pleissner, K.-P.; Schmid, M.; Brinkmann, V.; Naumann, M.; Rother, M.; Machuy, N.; Meyer, T. F.

doi:10.1101/139998

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bioRxiv · 10.1101/139998

ALPK1 And TIFA Dependent Innate Immune Response Triggered By The Helicobacter Pylori Type IV Secretion System

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Abstract

Activation of transcription factor NF-{kappa}B 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-1{beta}- and TNF-- dependent NF-{kappa}B 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-{beta}-D-manno-heptose 1,7-bisphosphate ({beta}HBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-{kappa}B activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-{kappa}B 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-{kappa}B activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogens T4SS.

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Zimmermann, S., Pfannkuch, L., Al-Zeer, M., Bartfeld, S., Koch, M., Liu, J., Rechner, C., Soerensen, M., Sokolova, O., Zamyatina, A., Kosma, P., Maeurer, A. P., Glowinski, F., Pleissner, K.-P., Schmid, M., Brinkmann, V., Naumann, M., Rother, M., Machuy, N., Meyer, T. F.. 2017-05-19. ALPK1 And TIFA Dependent Innate Immune Response Triggered By The Helicobacter Pylori Type IV Secretion System. https://doi.org/10.1101/139998

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