Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2,Redox Biology

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Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2
Redox Biology ( IF 10.7 ) Pub Date : 2021-10-03 , DOI: 10.1016/j.redox.2021.102160
Cheryl van de Wetering ₁ , Allison M Manuel ₂ , Mona Sharafi ₃ , Reem Aboushousha ₂ , Xi Qian ₂ , Cuixia Erickson ₂ , Maximilian MacPherson ₂ , Garrett Chan ₂ , Ian M Adcock ₄ , Nazanin ZounematKermani ₄ , Florence Schleich ₅ , Renaud Louis ₅ , Eric Bohrnsen ₆ , Angelo D'Alessandro ₆ , Emiel F Wouters ₇ , Niki L Reynaert ₈ , Jianing Li ₃ , C Roland Wolf ₉ , Colin J Henderson ₉ , Lennart K A Lundblad ₁₀ , Matthew E Poynter ₁₁ , Anne E Dixon ₁₁ , Charles G Irvin ₁₁ , Albert van der Vliet ₂ , Jos L van der Velden ₂ , Yvonne M Janssen-Heininger ₂

Affiliation

Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA; Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA.
Department of Chemistry, University of Vermont, Burlington, VT, USA.
National Heart & Lung Institute & Data Science Institute, Imperial College London, UK.
Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium.
Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States.
Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands; Ludwig Boltzmann Institute for Lung Health, Vienna, Austria.
Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Center, Ninewells Hospital Dundee DD1 9SY, Scotland, United Kingdom.
Meakins-Christie Laboratories, McGill University & THORASYS Thoracic Medical Systems Inc., Montréal, QC, Canada.
Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA.

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-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β 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-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. ¹³C-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.

中文翻译：

谷胱甘肽-S-转移酶 P 促进哮喘中与丙酮酸激酶 M2 氧化相关的糖酵解

背景

白介素 1 依赖性的糖酵解增加会促进小鼠过敏性气道疾病，而丙酮酸激酶 M2 (PKM2) 活性的破坏在此至关重要。谷胱甘肽-S-转移酶 P (GSTP) 与哮喘发病机制有关，并通过 S-谷胱甘肽化调节蛋白质的氧化状态。我们探讨了 GSTP 依赖性 S-谷胱甘肽化是否通过促进糖酵解重编程来促进过敏性气道疾病，以及它是否涉及 PKM2 的破坏。

方法

我们在 C57BL6/NJ WT 或缺乏 GSTP 的小鼠中使用屋尘螨 (HDM) 或白介素-1β。用 IL-1β 和选择性 GSTP 抑制剂 TLK199 刺激气道基底细胞。在哮喘患者和健康对照的痰样本中评估 GSTP 和 PKM2，并纳入 U-BIOPRED 严重哮喘队列数据库的分析。

结果

Gstp的消除降低了总 S-谷胱甘肽化并减轻了 HDM 诱导的过敏性气道疾病和白细胞介素 1β 介导的炎症。 Gstp缺失或 TLK199 抑制减少了上皮细胞白细胞介素 1β 刺激的促炎介质和乳酸的分泌。 ¹³ C-葡萄糖代谢组学显示丙酮酸激酶步骤中响应 TLK199 的糖酵解通量减少。与对照组相比，暴露于 HDM 的小鼠的 BAL 以及哮喘患者的痰液中 GSTP 和 PKM2 水平均升高。痰蛋白组学和转录组学揭示了哮喘中 GSTP、PKM2 和糖酵解途径之间的密切相关性。