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

Lamia Azzi-Martin, Wencan He, Christelle Péré-Védrenne, Victoria Korolik, Chloé Alix, Martina Prochazkova-Carlotti, Jean-Luc Morel, Emilie Le Roux-Goglin, Philippe Lehours, Mojgan Djavaheri-Mergny, Christophe F. Grosset, Christine Varon, Pierre Dubus, Armelle Ménard
PLoS Pathog. 2019-09-30; 15(9): e1007921
DOI: 10.1371/journal.ppat.1007921

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Azzi-Martin L(1), He W(1), Péré-Védrenne C(1), Korolik V(2), Alix C(1), Prochazkova-Carlotti M(1), Morel JL(3), Le Roux-Goglin E(1), Lehours P(1)(4), Djavaheri-Mergny M(5), Grosset CF(6), Varon C(1), Dubus P(1)(7), Ménard A(1).

Author information:
(1)Univ. Bordeaux, INSERM, Bordeaux Research in Translational Oncology, BaRITOn, U1053, Bordeaux, France.
(2)Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, Australia.
(3)Univ. Bordeaux, CNRS; UMR5293, Institut des maladies neurodégénératives, Bordeaux, France.
(4)CHU de Bordeaux, Laboratoire de Bactériologie, Centre National de Référence des Campylobacters et des Hélicobacters, Bordeaux, France.
(5)Univ. Bordeaux, INSERM U1218 ACTION, Institut Bergonié, Bordeaux France, INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
(6)Univ. Bordeaux, INSERM, Biothérapies des Maladies Génétiques, Inflammatoires et Cancer, BMGIC, U1035, Bordeaux, France.
(7)CHU de Bordeaux, Pôle biologie et pathologie, Service de biologie des tumeurs, Bordeaux, France.

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.

Auteurs Bordeaux Neurocampus