Séminaire Amel Mettouchi

ExPEC/UPEC pathotypes of Escherichia coli, that belong to the phylogroup B2, can express the cytotoxic necrotizing factor 1 (CNF1) cyclomodulin, a toxin that deamidates a specific glutamine residue in small Rho GTPases (Q61 in Rac1, CDC42 and Q63 in RhoA). This posttranslational modification impairs the intrinsic and GAP-stimulated GTPase activity of Rho proteins, thereby inducing the constitutive stimulation of their downstream signaling pathways. The host cell can perceive the sustained activation state of Rac1 and maintain homeostasis by a selective targeting of GTP-bound Rac1 to ubiquitin-mediated proteasomal degradation. This is achieved by the tumor suppressor E3 ubiquitin-ligase HACE1. We recently discovered that HACE1-mediated proteasomal degradation of Rac1 is connected to tissue stiffness sensing by the HACE1 partner Optineurin. We thereby uncovered a signaling hub connecting Rac1 activity to integrin mechanical activation and mechanosignaling involved in the control of cell cycle progression and diverted by invasive E. coli to penetrate cells.
Using animal models and patient-derived material to get an integrated pathophysiological insight into CNF1 functions, we uncovered the important role played by CNF1 toxin for competitive colonization of the gut by MDR ExPEC strains from the ST131 sequence type, linked to its deamidase activity and capacity of bacteria to invade colonic tissues. Our ongoing studies show the increased carriage of cnf1-encoding bacteria in the fecal and colonic mucosa-associated microbiota of patients suffering from colorectal cancer (CRC) as compared to controls. Collectively these data point to the importance of investigating possible detrimental effects of CNF1 on the gut epithelium, that may contribute to the onset or progression of CRC. Here, I will present our studies in mouse intestinal organoids and a model of cnf1+ E. coli-colonized HACE1 knockout mice.