Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3β to impede lung epithelial cell migration
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Published on: October 13, 2019
Xiuying Li1, Yandong Lai1, Jin Li1
1Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Abstract:
Oxidative stress impacts normal cellular function leading to the pathogenesis of various diseases including pulmonary illnesses. Protein arginine methyltransferase 4 (PRMT4) is critical for normal lung alveolar epithelial cell development; however, the regulation of PRMT4 within such pulmonary diseases has yet to be elucidated. Using biochemical approaches, we uncovered that peroxide (H2O2) treatment decreases PRMT4 protein stability in murine lung epithelial (MLE12) cells to impede cell migration. Protein kinase glycogen synthase kinase 3β (GSK-3β) interacts with PRMT4 and catalyzes PRMT4 T132 phosphorylation that protects PRMT4 from ubiquitin proteasomal degradation. H2O2 downregulates GSK-3β to reduce PRMT4 at protein level. PRMT4 promotes cell migration and H2O2 degrades PRMT4 to inhibit lung epithelial cell migration. These observations demonstrate that oxidative stress destabilizes PRMT4 via GSK-3β signaling to impede lung epithelial cell migration that may hinder the lung repair and regeneration process.
Insights
Oxidative stress reduces protein arginine methyltransferase 4 (PRMT4) stability in lung cells by downregulating GSK-3β. This destabilization inhibits cell migration, potentially impairing lung repair.
Area of Science:
- Cellular Biology
- Molecular Biology
- Pulmonary Medicine
Background:
- Oxidative stress contributes to pulmonary diseases by disrupting normal cellular function.
- Protein arginine methyltransferase 4 (PRMT4) is essential for lung alveolar epithelial cell development.
- The regulation of PRMT4 in pulmonary disease pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of PRMT4 regulation in response to oxidative stress in lung epithelial cells.
- To elucidate the mechanism by which oxidative stress affects PRMT4 stability and function.
- To determine the impact of PRMT4 destabilization on lung epithelial cell migration.
Main Methods:
- Biochemical approaches were used to study PRMT4 stability and interactions.
- Murine lung epithelial (MLE12) cells were treated with hydrogen peroxide (H2O2) to induce oxidative stress.
- Protein levels, stability, phosphorylation, and cell migration were assessed.
Main Results:
- Hydrogen peroxide (H2O2) treatment decreased PRMT4 protein stability in MLE12 cells.
- Glycogen synthase kinase 3β (GSK-3β) interacts with and phosphorylates PRMT4 at T132, protecting it from degradation.
- H2O2 downregulates GSK-3β, leading to reduced PRMT4 protein levels and inhibited cell migration.
Conclusions:
- Oxidative stress destabilizes PRMT4 through GSK-3β signaling in lung epithelial cells.
- Reduced PRMT4 protein levels impede lung epithelial cell migration.
- This mechanism may hinder lung repair and regeneration processes in pulmonary diseases.
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