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Élucidation du rôle des phosphatases membranaires dépendantes de l'undécaprényl pyrophosphate dans la pathogénèse d'Helicobacter pylori

Abstract : The biogenesis of all the bacterial cell-envelope polysaccharides requires the translocation, across the plasma membrane, of sugar sub-units that are produced inside the cytoplasm. To this end, the hydrophilic sugars must be anchored to a lipid phosphate carrier (undecaprenyl phosphate (C55-P)), yielding membrane intermediates, which are translocated to the outer face of the membrane. Finally, the glycan moiety is transferred to a nascent acceptor polymer, releasing the carrier in the "inactive" undecaprenyl diphosphate (C55-PP) form. Thus, C55-P is synthesized through the dephosphorylation of C55-PP, itself arising from either de novo synthesis or recycling. Two types of integral membrane C55-PP phosphatases were described: BacA enzymes, which constitute a family of uncharacterized phosphatases, and a sub-group of PAP2 enzymes (type 2 phosphatidic acid phosphatases). The human pathogen Helicobacter pylori, does not contain BacA but has four membrane PAP2 proteins: HP0021, HP0350, HP1580 and HP0851. Further studies have revealed remarkable features of PAP2 enzymes such as dual functions and phosphotransfer side-activities. HP0021 and HP1580 from H. pylori modify lipid A via dephosphorylation reactions, yielding a dephosphorylated form of lipid A that is required for H. pylori to survive in the gastric mucosa, by conferring CAMPS resistance and escape to the host immune system. These enzymes are essential for the synthesis of various cell wall polymers by the (re)generation of C55-P, but they also participate in other lipids biosynthesis and to different networks of cell envelope modifications that can deeply modulate cell physiology. The project aims at deciphering the physiological role of these 4 phosphatases via multiple and complementary approaches ranging from a detailed biochemical and structural characterization to the assessment of their impact on cell envelope metabolism, bacterial fitness and microbe-host interactions.
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Elise Gasiorowski. Élucidation du rôle des phosphatases membranaires dépendantes de l'undécaprényl pyrophosphate dans la pathogénèse d'Helicobacter pylori. Microbiologie et Parasitologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB073⟩. ⟨tel-02510950⟩

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