Abstract
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.
| Original language | English |
|---|---|
| Article number | e102166 |
| Journal | EMBO Journal |
| Volume | 39 |
| Issue number | 8 |
| ISSN | 0261-4189 |
| DOIs | |
| Publication status | Published - 15.04.2020 |
Funding
We thank Anke Hellberg and B?atrice Niragire for technical assistance, Manuela D'Eletto for TG2?/? reconstituted MEFs, Dr Christina Papista for providing mice, Dr Denise Badet-Denisot for the rhGFPT1 plasmid and for advice, Dr Cora Weigert for anti-GFPT antibodies, Vishu Aimanianda Bopaiah for help with HPAEC, Dr Lingling Chen for CmGroEL, and Augustin Latourte for RoActemra?. 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 Minist?re de l'Education Nationale, de la Recherche et de la Technologie, and by Canc?ropole Ile-de-France.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
