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    CNF1 toxin from pathogenic Escherichia coli: apprehending proteasomal degradation of Rho GTPases in infection and cancer

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    Séminaire de l'Institut Cochin

    Jeudi 29 novembre 2018 - 12h00 - Salle de conférence Rosalind Franklin, 2ème étage

     


    Emmanuel Lemichez

    Département de Microbiologie, Institut Pasteur, Paris, France

     

     invité par Evelyne Bloch-Gallego

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

     Our work has contributed to establish the remarkable convergence of bacterial virulence towards the Rho family of small GTPases, which are subjected to post-translational modifications by bacterial toxins to corrupt host defenses, promote bacterial invasion & survival and also trigger bacterial dissemination in tissues. These small GTPases are critical host factors controlling cell growth, architecture and plasticity, as well as inflammatory reactions. Study of this pathway is of great promise to clarify critical determinants in host-pathogen interactions and the interplay of Rac1 signaling in a broad number of non-communicable human diseases notably cancer. The CNF1 toxin from pathogenic E. coli of the phylogenic group B2 is a virulence factor that catalyzes the gain-of-function mutation Q61E on Rac1 and the equivalent on other small Rho GTPases. Our studies on CNF1 toxin have been instrumental in deciphering a critical layer of regulation of the flux of active Rho GTPases via ubiquitin-mediated proteasomal degradation. This breakthrough was followed by the identification by our group of HACE1 as a critical E3 ubiquitin-ligase (E3L) targeting activated Rac1 downstream CNF1, but also other Rac1 cellular activators. Since these pioneering discoveries, HACE1 deregulations have been documented in inflammation, developmental disorders, cancer onset and progression. Most recently, analysis of HACE1 KO mice pinpointed the critical function of HACE1 as gatekeeper of TNFR1-induced cell fate, and its requirement to control bacterial infection.

     

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