The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress.

Authors:
Michael Bauer, Zuzana Nascakova, Anca-Irina Mihai, Phil F Cheng, Mitchell P Levesque, Simon Lampart, Robert Hurwitz, Lennart Pfannkuch, Jana Dobrovolna, Melanie Jacobs, Sina Bartfeld, Anders Dohlman, Xiling Shen, Alevtina A Gall, Nina R Salama, Antonia Töpfer, Achim Weber, Thomas F Meyer, Pavel Janscak, Anne Müller
Year of publication:
2020
Volume:
11
Issue:
1
Issn:
2041-1723
Journal title abbreviated:
NAT COMMUN
Journal title long:
Nature communications
Impact factor:
14.919
Abstract:
Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.