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Investigation of the role of tissue transglutaminase (TG2) in the infection by Chlamydia trachomatis : a key player in the metabolic rewiring of the host cell

Abstract : Chlamydia trachomatis is an obligate intracellular pathogenic bacterium infecting humans, causing sexually transmitted infections or ocular infections. During its biphasic developmental cycle, C. trachomatis remains in a membrane-bound compartment, separated from the cytoplasm. The bacterium has acquired strategies to highjack cellular functions to meet its metabolic needs. Here we focused on the impact of a cellular enzyme called TG2 on C. trachomatis development. The activity of this enzyme is a transamidating activity, i.e. the catalysis of a covalent bound between two proteins or with a small amine present in the cell. We have shown that TG2 expression and transamidating activity increased upon C. trachomatis infection, necessary for optimal bacterial growth. At the cellular level, we focused our work on the impact of TG2 on cellular metabolism modification during infection. We showed that TG2 played a central role in the control of glucose import in infected cells. In addition, we identified GFPT1, as a target of TG2. GFPT1 is the rate-limiting enzyme of the hexosamine biosynthetic pathway, regulating the synthesis of UDP-N-acetylglucosamine. This metabolite is used for post-translational modification of proteins by O-GlcNAcylation. Our work uncovered a link between TG2 transamidating activity and O-GlcNAcylation. This link was disrupted in infected cells likely because UDP-N-acetylglucosamine is consumed by the bacteria to assist division. In conclusion, our work established TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain its own metabolic needs.
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Benoit Maffei. Investigation of the role of tissue transglutaminase (TG2) in the infection by Chlamydia trachomatis : a key player in the metabolic rewiring of the host cell. Cellular Biology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS532⟩. ⟨tel-02926841⟩

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