The Ancestral N-Terminal Domain of Big Defensins Drives Bacterially Triggered Assembly into Antimicrobial Nanonets

• Published in: mBio
• Main Authors: Loth, Karine, Vergnes, Agnès, Barreto, Cairé, Voisin, Sébastien, Meudal, Herve, Da Silva, Jennifer, Bressan, Albert, Belmadi, Nawal, Bachère, Evelyne, Aucagne, Vincent, Cazevielle, Chantal, Marchandin, Hélène, Rosa, Rafael Diego, Bulet, Philippe, Touqui, Lhousseine, DELMAS, Agnès, Destoumieux-Garzon, Delphine
• Other Authors: Centre de biophysique moléculaire (CBM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire Grenoble (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
• Format: Article in Journal/Newspaper
• Language: English
• Published: HAL CCSD 2019
• Subjects: [SDV]Life Sciences [q-bio]; Crassostrea gigas
• Online Access: https://hal.archives-ouvertes.fr/hal-02994659; https://hal.archives-ouvertes.fr/hal-02994659/document; https://hal.archives-ouvertes.fr/hal-02994659/file/mBio-2019-Loth-e01821-19.full%20copie.pdf; https://doi.org/10.1128/mBio.01821-19

International audience Big defensins, ancestors of ␤-defensins, are composed of a ␤-defensin-like C-terminal domain and a globular hydrophobic ancestral N-terminal domain. This unique structure is found in a limited number of phylogenetically distant species , including mollusks, ancestral chelicerates, and early-branching cephalochor-dates, mostly living in marine environments. One puzzling evolutionary issue concerns the advantage for these species of having maintained a hydrophobic domain lost during evolution toward ␤-defensins. Using native ligation chemistry, we produced the oyster Crassostrea gigas BigDef1 (Cg-BigDef1) and its separate domains. Cg-BigDef1 showed salt-stable and broad-range bactericidal activity, including against multidrug-resistant human clinical isolates of Staphylococcus aureus. We found that the ancestral N-terminal domain confers salt-stable antimicrobial activity to the ␤-defensin-like domain, which is otherwise inactive. Moreover, upon contact with bacteria, the N-terminal domain drives Cg-BigDef1 assembly into nanonets that entrap and kill bacteria. We speculate that the hydrophobic N-terminal domain of big defensins has been retained in marine phyla to confer salt-stable interactions with bacterial membranes in environments where electrostatic interactions are impaired. Those remarkable properties open the way to future drug developments when physiological salt concentrations inhibit the antimicrobial activity of vertebrate ␤-defensins. IMPORTANCE ␤-Defensins are host defense peptides controlling infections in species ranging from humans to invertebrates. However, the antimicrobial activity of most human ␤-defensins is impaired at physiological salt concentrations. We explored the properties of big defensins, the ␤-defensin ancestors, which have been conserved in a number of marine organisms, mainly mollusks. By focusing on a big defensin from oyster (Cg-BigDef1), we showed that the N-terminal domain lost during evolution toward ␤-defensins confers bactericidal activity to ...