| First Author | van de Wetering C | Year | 2021 |
| Journal | Redox Biol | Volume | 47 |
| Pages | 102160 | PubMed ID | 34624602 |
| Mgi Jnum | J:319417 | Mgi Id | MGI:6787916 |
| Doi | 10.1016/j.redox.2021.102160 | Citation | van de Wetering C, et al. (2021) Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2. Redox Biol 47:102160 |
| abstractText | BACKGROUND: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. METHODS: We used house dust mite (HDM) or interleukin-1beta in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1beta and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. RESULTS: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1beta-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1beta-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. (13)C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. CONCLUSIONS: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease. |
