MATE transport of the E-coli-derived genotoxin colibactin
2016
Mousa, Jarrod J. | Yang, Ye | Tomkovich, Sarah | Shima, Ayaka | Newsome, Rachel C. | Tripathi, Prabhanshu | Oswald, Eric | Bruner, Steven D. | Jobin, Christian | Department of Chemistry [Gainesville] (UF|Chemistry) ; University of Florida [Gainesville] (UF) | Department of Medicine [Gainesville] (UF|Medicine) ; University of Florida [Gainesville] (UF) | Institut National de la Recherche Agronomique (INRA) | Service Bactériologie et hygiène [CHU Toulouse] ; Institut Fédératif de Biologie (IFB) ; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse] ; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) | Centre de Physiopathologie Toulouse Purpan (CPTP) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Institut National de la Santé et de la Recherche Médicale (INSERM) | Department Chemistry ; Swedish University of Agricultural Sciences = Sveriges lantbruksuniversitet (SLU) | Interactions hôtes-agents pathogènes [Toulouse] (IHAP) ; Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT) | University of Florida [Gainesville] (UF) | Department Medicine ; Universität Salzburg | University of Florida UF DoM Gatorade Fund R01 DK73338 R01DK47700 R01 GM0865700
International audience
Afficher plus [+] Moins [-]anglais. Various forms of cancer have been linked to the carcinogenic activities of microorganisms(1-3). The virulent gene island polyketide synthase (pks) produces the secondary metabolite colibactin, a genotoxic molecule(s) causing double-stranded DNA breaks(4) and enhanced colorectal cancer development(5,6). Colibactin biosynthesis involves a prodrug resistance strategy where an N-terminal prodrug scaffold (precolibactin) is assembled, transported into the periplasm and cleaved to release the mature product(7-10). Here, we show that ClbM, a multidrug and toxic compound extrusion (MATE) transporter, is a key component involved in colibactin activity and transport. Disruption of clbM attenuated pks+ E. coli-induced DNA damage in vitro and significantly decreased the DNA damage response in gnotobiotic Il10(-/-) mice. Colonization experiments performed in mice or zebrafish animal models indicate that clbM is not implicated in E. coli niche establishment. The X-ray structure of ClbM shows a structural motif common to the recently described MATE family. The 12-transmembrane ClbM is characterized as a cation-coupled antiporter, and residues important to the cation-binding site are identified. Our data identify ClbM as a precolibactin transporter and provide the first structure of a MATE transporter with a defined and specific biological function.
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