The Nuclear Remodeling Induced by Helicobacter Cytolethal Distending Toxin Involves MAFB Oncoprotein
Christelle Péré-Védrenne,
Wencan He,
Lamia Azzi-Martin,
Valérie Prouzet-Mauléon,
Alice Buissonnière,
Bruno Cardinaud,
Philippe Lehours,
Francis Mégraud,
Christophe F. Grosset,
Armelle Ménard
Affiliations
Christelle Péré-Védrenne
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Wencan He
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Lamia Azzi-Martin
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Valérie Prouzet-Mauléon
Université de Bordeaux, TBMCore, CRISP’edit, TBMcore CNRS-Centre National de la Recherche Scientifique UMS3427/INSERM—Institut National de la Santé et de la Recherche Médicale US005, 33076 Bordeaux, France
Alice Buissonnière
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Bruno Cardinaud
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, ACTION, U1218, Institut Bergonié, 33076 Bordeaux, France
Philippe Lehours
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Francis Mégraud
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Christophe F. Grosset
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BMGIC—Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancer, U1035, miRCaDe Team, 33076 Bordeaux, France
Armelle Ménard
Université de Bordeaux, INSERM—Institut National de la Santé et de la Recherche Médicale, BaRITOn—Bordeaux Research in Translational Oncology, UMR1053, 33076 Bordeaux, France
Enterohepatic Helicobacters, such as Helicobacter hepaticus and Helicobacter pullorum, are associated with several intestinal and hepatic diseases. Their main virulence factor is the cytolethal distending toxin (CDT). In the present study, whole genome microarray-based identification of differentially expressed genes was performed in vitro in HT-29 intestinal cells while following the ectopic expression of the active CdtB subunit of H. hepaticus CDT. A CdtB-dependent upregulation of the V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene encoding the MAFB oncoprotein was found, as well as the CdtB-dependent regulation of several MAFB target genes. The transduction and coculture experiments confirmed MAFB mRNA and protein induction in response to CDT and its CdtB subunit in intestinal and hepatic cell lines. An analysis of MAFB protein subcellular localization revealed a strong nuclear and perinuclear localization in the CdtB-distended nuclei in intestinal and hepatic cells. MAFB was also detected at the cell periphery of the CdtB-induced lamellipodia in some cells. The silencing of MAFB changed the cellular response to CDT with the formation of narrower lamellipodia, a reduction of the increase in nucleus size, and the formation of less γH2AX foci, the biomarker for DNA double-strand breaks. Taken together, these data show that the CDT of enterohepatic Helicobacters modulates the expression of the MAFB oncoprotein, which is translocated in the nucleus and is associated with the remodeling of the nuclei and actin cytoskeleton.
