1. Infection-driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells
- Author
-
Benoit Maffei, Mariette Matondo, Magalie Duchateau, Jeffrey W. Keillor, Stéphanie Perrinet, Sébastien Triboulet, Yongzheng Wu, Jan Rupp, Marc Laverrière, Robert L Hollis, Charlie Gourley, Agathe Subtil, Biologie cellulaire de l'Infection microbienne, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège doctoral [Sorbonne universités], Sorbonne Universités, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Edinburgh Cancer Research UK Centre [Edinburgh, UK], University of Edinburgh-MRC Institute of Genetics and Molecular Medicine [Edinburgh], Universität zu Lübeck [Lübeck], University of Ottawa [Ottawa] (uOttawa), This work was supported by an ERC Starting Grant (NUChLEAR N°282046), the Institut Pasteur (GFP‐LIMNEC METINF), the Centre National de la Recherche Scientifique, and GEFLUC. BM was funded by the Ministère de l'Education Nationale, de la Recherche et de la Technologie, and by Cancéropole Ile‐de‐France., European Project: 282046,ERC,ERC-2011-StG_20101109,NUCHLEAR, Biologie cellulaire de l'Infection microbienne - Cellular Biology of Microbial Infection, Sorbonne Université (SU), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Cancer Research UK Edinburgh Centre [Edinburgh, UK], University of Edinburgh-MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council-Medical Research Council, University of Ottawa [Ottawa], Huawei Technologies [Shanghaï], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Interactions Cellulaires (BIC), Spectrométrie de Masse structurale et protéomique, Plateforme de Protéomique / Proteomics platform, Centre National de la Recherche Scientifique (CNRS)-Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège Doctoral, Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Universität zu Lübeck = University of Lübeck [Lübeck]
- Subjects
Tissue transglutaminase ,Glucose uptake ,Chlamydia trachomatis ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,O-GlcNAcylation ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Chlamydia ,GFPT ,Mice, Knockout ,chemistry.chemical_classification ,Glucosamine ,0303 health sciences ,General Neuroscience ,Fructosephosphates ,Articles ,3. Good health ,Cell biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Biology ,Gene Expression Regulation, Enzymologic ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Biosynthesis ,GTP-Binding Proteins ,Glucose import ,Animals ,Humans ,Protein Glutamine gamma Glutamyltransferase 2 ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,030304 developmental biology ,Transglutaminases ,General Immunology and Microbiology ,Intracellular parasite ,Glucose transporter ,hexosamine biosynthesis ,Biological Transport ,Epithelial Cells ,Hexosamines ,Chlamydia Infections ,Fibroblasts ,transglutaminase 2 ,Mice, Inbred C57BL ,Metabolic pathway ,Glucose ,Enzyme ,chemistry ,biology.protein ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
DATA AVAILABILITYThe mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD017117.; International audience; Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme with transamidating activity. We report here that both expression and activity of TG2 are enhanced in mammalian epithelial cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 impairs bacterial development. We show that TG2 increases glucose import by up-regulating the transcription of the glucose transporter genes GLUT-1 and GLUT-3. Furthermore, TG2 activation drives one specific glucose-dependent pathway in the host, i.e., hexosamine biosynthesis. Mechanistically, we identify the glucosamine:fructose-6-phosphate amidotransferase (GFPT) among the substrates of TG2. GFPT modification by TG2 increases its enzymatic activity, resulting in higher levels of UDP-N-acetylglucosamine biosynthesis and protein O-GlcNAcylation. The correlation between TG2 transamidating activity and O-GlcNAcylation is disrupted in infected cells because host hexosamine biosynthesis is being exploited by the bacteria, in particular to assist their division. In conclusion, our work establishes TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain their own metabolic needs.
- Published
- 2020