Cytolethal distending toxin induces the formation of transient messenger-rich ribonucleoprotein nuclear invaginations in surviving cells

• Published in: PLoS pathogens Vol. 15; no. 9; p. e1007921
• Main Authors: Azzi-Martin, Lamia, He, Wencan, Péré-Védrenne, Christelle, Korolik, Victoria, Alix, Chloé, Prochazkova-Carlotti, Martina, Morel, Jean-Luc, Le Roux-Goglin, Emilie, Lehours, Philippe, Djavaheri-Mergny, Mojgan, Grosset, Christophe F, Varon, Christine, Dubus, Pierre, Ménard, Armelle
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.09.2019; Public Library of Science (PLoS)
• Subjects: Animal biology; Animal experimentation; Animal models; Animals; Bacteria; Bacterial infections; Bacterial toxins; Bacterial Toxins - toxicity; Biochemistry, Molecular Biology; Biology and life sciences; Calcium; Calcium signalling; Campylobacter; Cancer; Carcinogens; Cell culture; Cell cycle; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell Survival; Chemical properties; Cytolethal distending toxin; Deoxyribonucleic acid; DNA; DNA Damage; Genomes; Genomics; Genotoxicity; Giant cells; Health aspects; Helicobacter - pathogenicity; Helicobacter Infections - metabolism; Helicobacter Infections - pathology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Insulation; Intestine; Invaginations; Life Sciences; MAP kinase; Messenger RNA; Mice; Mice, Inbred C57BL; Microscopy; Microscopy, Electron, Transmission; mRNA turnover; Mutagens - toxicity; Neurons and Cognition; Nuclei (cytology); Oncology; Pathogens; Peptides - toxicity; Pharmaceutical sciences; Ploidy; Polyadenylation; Polyketides - toxicity; Proteins; Research and analysis methods; Ribonucleoproteins; Ribonucleoproteins - metabolism; Ribosomes; RNA; RNA, Messenger - metabolism; Structure; Tetracyclines; Toxins; Translation; Translation (Genetics); Xenografts; Xenotransplantation; France
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007921

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture experiments with CDT- and colibactin-secreting bacteria and hepatic, intestinal and gastric cells, and xenograft mouse-derived models were used to assess the nuclear remodeling in vitro and in vivo. Our results showed that CDT and colibactin induced-nuclear remodeling can be associated with the formation of deep cytoplasmic invaginations in the nucleus of giant cells. These structures, observed both in vivo and in vitro, correspond to nucleoplasmic reticulum (NR). The core of the NR was found to concentrate ribosomes, proteins involved in mRNA translation, polyadenylated RNA and the main components of the complex mCRD involved in mRNA turnover. These structures are active sites of mRNA translation, correlated with a high degree of ploidy, and involve MAPK and calcium signaling. Additional data showed that insulation and concentration of these adaptive ribonucleoprotein particles within the nucleus are dynamic, transient and protect the cell until the genotoxic stress is relieved. Bacterial genotoxins-induced NR would be a privileged gateway for selected mRNA to be preferably transported therein for local translation. These findings offer new insights into the context of NR formation, a common feature of many cancers, which not only appears in response to therapies-induced DNA damage but also earlier in response to genotoxic bacteria.