The CDT of Helicobacter hepaticus induces pro-survival autophagy and nucleoplasmic reticulum formation concentrating the RNA binding proteins UNR/CSDE1 and P62/SQSTM1

• Published in: PLoS pathogens Vol. 17; no. 3; p. e1009320
• Main Authors: He, Wencan, Azzi-Martin, Lamia, Velasco, Valérie, Lehours, Philippe, Dubus, Pierre, Djavaheri-Mergny, Mojgan, Ménard, Armelle
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2021; Public Library of Science (PLoS)
• Subjects: Abbreviations; Analysis; Apoptosis; Aspartic acid; Autophagy; Autophagy (Cytology); Binding; Binding proteins; Biology and Life Sciences; Biosynthesis; Calcium; Cancer; Catalytic activity; Cell cycle; Cell death; Cell survival; Chains; Cholesterol; Coils; Damage; Deoxyribonucleic acid; DNA; DNA damage; DNA microarrays; DNA repair; Domains; E coli; Ectopic expression; Fluorescence; Forkhead protein; FOXO1 protein; Gene expression; Genes; Genetic aspects; Genomes; Grb2 protein; Growth factors; Helicobacter; Helicobacter infections; Homology; Hypoxia; Initiation factor eIF-2; Inositol 1,4,5-trisphosphate receptors; Insulation; Intestine; Intoxication; Kinases; Life Sciences; Medicine and Health Sciences; Membrane proteins; Membranes; Phagocytosis; Polyploidy; Protein-serine/threonine kinase; Proteins; Rapamycin; Receptors; Research and analysis methods; Retina; Retinoblastoma; RNA; RNA-binding protein; Survival; Transcription; Ubiquitin-protein ligase; Zinc finger proteins; γ-Aminobutyric acid; France
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009320

Humans are frequently exposed to bacterial genotoxins of the gut microbiota, such as colibactin and cytolethal distending toxin (CDT). In the present study, whole genome microarray-based identification of differentially expressed genes was performed in vitro on HT29 intestinal cells while following the ectopic expression of the active CdtB subunit of Helicobacter hepaticus CDT. Microarray data showed a CdtB-dependent upregulation of transcripts involved in positive regulation of autophagy concomitant with the downregulation of transcripts involved in negative regulation of autophagy. CdtB promotes the activation of autophagy in intestinal and hepatic cell lines. Experiments with cells lacking autophagy related genes, ATG5 and ATG7 infected with CDT- and colibactin-producing bacteria revealed that autophagy protects cells against the genotoxin-induced apoptotic cell death. Autophagy induction could also be associated with nucleoplasmic reticulum (NR) formation following DNA damage induced by these bacterial genotoxins. In addition, both genotoxins promote the accumulation of the autophagic receptor P62/SQSTM1 aggregates, which colocalized with foci concentrating the RNA binding protein UNR/CSDE1. Some of these aggregates were deeply invaginated in NR in distended nuclei together or in the vicinity of UNR-rich foci. Interestingly, micronuclei-like structures and some vesicles containing chromatin and γH2AX foci were found surrounded with P62/SQSTM1 and/or the autophagosome marker LC3. This study suggests that autophagy and P62/SQSTM1 regulate the abundance of micronuclei-like structures and are involved in cell survival following the DNA damage induced by CDT and colibactin. Similar effects were observed in response to DNA damaging chemotherapeutic agents, offering new insights into the context of resistance of cancer cells to therapies inducing DNA damage.