@article{ef05908738bd492fb659a399d3e94286,
title = "Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2",
abstract = "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-1 beta in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1 beta 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-1 beta-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin1 beta-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. C-13-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.",
keywords = "Allergic airways disease, House dust mite, Interleukin-1 beta, S-glutathionylation, Thymic stromal lymphopoietin, GSTM1, PKM2, RISK, POLYMORPHISMS, LOCALIZATION, METAANALYSIS, CONTRIBUTES, EXPRESSION, PHENOTYPES, RESISTANCE",
author = "{van de Wetering}, C. and A.M. Manuel and M. Sharafi and R. Aboushousha and X. Qian and C. Erickson and M. MacPherson and G. Chan and I.M. Adcock and N. ZounematKermani and F. Schleich and R. Louis and E. Bohrnsen and A. D'Alessandro and E.F. Wouters and N.L. Reynaert and J.N. Li and C.R. Wolf and C.J. Henderson and L.K.A. Lundblad and M.E. Poynter and A.E. Dixon and C.G. Irvin and {van der Vliet}, A. and {van der Velden}, J.L. and Y.M. Janssen-Heininger",
note = "Funding Information: This work was supported by grants NIH R01 HL137268 , R35HL135828 (Y-JH), an unrestricted grant from Chiesi (EW) , and Cancer Center Support Grant P30CA046934 (AD{\textquoteright}A). We acknowledge the technical expertise of J. Bates, N. Daphtary and M. Aliyeva with AHR analysis. Imaging was performed in the Microscopy Imaging Center at the University of Vermont (RRID# SCR_018821 ), and we also acknowledge the Larner College of Medicine Shared Instrumentation Award. U-BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010 ), resources from the European Union's Seventh Framework Programme ( FP7/2007–2013 ) and EFPIA companies' in-kind contribution ( www.imi.europa.eu ). The computational resources were provided by the Vermont Advanced Computer Core. Funding Information: This work was supported by grants NIH R01 HL137268, R35HL135828 (Y-JH), an unrestricted grant from Chiesi (EW), and Cancer Center Support Grant P30CA046934 (AD'A). We acknowledge the technical expertise of J. Bates, N. Daphtary and M. Aliyeva with AHR analysis. Imaging was performed in the Microscopy Imaging Center at the University of Vermont (RRID# SCR_018821), and we also acknowledge the Larner College of Medicine Shared Instrumentation Award. U-BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No.115010), resources from the European Union's Seventh Framework Programme (FP7/2007?2013) and EFPIA companies' in-kind contribution (www.imi.europa.eu). The computational resources were provided by the Vermont Advanced Computer Core. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = nov,
day = "1",
doi = "10.1016/j.redox.2021.102160",
language = "English",
volume = "47",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier Science",
}