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

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-?B signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate ?-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 ?-ADP-heptose/ ALPK1/TIFA/NF-?B 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-?B-driven innate immune responses to R-loop-dependent replication stress and DNA damage.

SUBMITTER: Bauer M

PROVIDER: S-EPMC7547021 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Bauer Michael M Nascakova Zuzana Z Mihai Anca-Irina AI Cheng Phil F PF Levesque Mitchell P MP Lampart Simon S Hurwitz Robert R Pfannkuch Lennart L Dobrovolna Jana J Jacobs Melanie M Bartfeld Sina S Dohlman Anders A Shen Xiling X Gall Alevtina A AA Salama Nina R NR Töpfer Antonia A Weber Achim A Meyer Thomas F TF Janscak Pavel P Müller Anne A

Nature communications 20201009 1

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 replicat ...[more]

PMID: 33037203

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Project description:Muscles of sarcopenic people show hypotrophic myofibers and infiltration with adipose and, at later stages, fibrotic tissue. The origin of infiltrating adipocytes resides in fibro-adipogenic precursors and nonmyogenic mesenchymal progenitor cells, and in satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5+ progenitor cell: the cell fate depends on levels of bone morphogenetic protein 7 (BMP-7), a TGF-β family member. S100B, a Ca2+-binding protein of the EF-hand type, is expressed at relatively high levels in myoblasts from sarcopenic humans and exerts anti-myogenic effects via NF-κB-dependent inhibition of MyoD, a myogenic transcription factor acting upstream of the essential myogenic factor, myogenin. Adipogenesis requires high levels of ROS, and myoblasts of sarcopenic subjects show elevated ROS levels. Here we show that: (1) ROS overproduction in myoblasts results in upregulation of S100B levels via NF-κB activation; and (2) ROS/NF-κB-induced accumulation of S100B causes myoblast transition into brown adipocytes. S100B activates an NF-κB/Ying Yang 1 axis that negatively regulates the promyogenic and anti-adipogenic miR-133 with resultant accumulation of the brown adipogenic transcription regulator, PRDM-16. S100B also upregulates BMP-7 via NF-κB/Ying Yang 1 with resultant BMP-7 autocrine activity. Interestingly, myoblasts from sarcopenic humans show features of brown adipocytes. We also show that S100B levels and NF-κB activity are elevated in brown adipocytes obtained by culturing myoblasts in adipocyte differentiation medium and that S100B knockdown or NF-κB inhibition in myoblast-derived brown adipocytes reconverts them into fusion-competent myoblasts. At last, interstitial cells and, unexpectedly, a subpopulation of myofibers in muscles of geriatric but not young mice co-express S100B and the brown adipocyte marker, uncoupling protein-1. These results suggest that S100B is an important intracellular molecular signal regulating Myf5+ progenitor cell differentiation into fusion-competent myoblasts or brown adipocytes depending on its levels.

Dataset Information

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

Publications

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

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