Endoplasmic Reticulum Oxidative Stress Promotes Glutathione-Dependent Oxidation of Collagen-1A1 and Promotes Lung Fibroblast Activation

• Published in: American journal of respiratory cell and molecular biology Vol. 71; no. 5; pp. 589 - 602
• Main Authors: Druso, Joseph E., MacPherson, Maximilian B., Chia, Shi B., Elko, Evan, Aboushousha, Reem, Seward, David J., Abdelhamid, Hend, Erickson, Cuixia, Corteselli, Elizabeth, Tarte, Megan, Peng, Zhihua, Bernier, Daniel, Zito, Ester, Shoulders, Matthew D., Thannickal, Victor J., Huang, Steven, van der Vliet, Albert, Anathy, Vikas, Janssen-Heininger, Yvonne M.W.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.11.2024
• Subjects: Collagen (type I); Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain; Collagenase; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; Extracellular matrix; Fibroblasts - metabolism; Fibrosis; Glutaredoxin; Glutaredoxins - genetics; Glutaredoxins - metabolism; Glutathione; Glutathione - metabolism; Humans; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Lung - metabolism; Lung - pathology; Lung diseases; Membrane Glycoproteins; Original Research; Oxidation-Reduction; Oxidative Stress; Oxidoreductases - genetics; Oxidoreductases - metabolism; Peroxiredoxins; Pulmonary fibrosis; Transcription activation; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; mechanosensing; idiopathic pulmonary fibrosis; glutaredoxin; glutathionylation; redox
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2023-0379OC

Changes in the oxidative (redox) environment accompany idiopathic pulmonary fibrosis (IPF). S-glutathionylation of reactive protein cysteines is a post-translational event that transduces oxidant signals into biological responses. We recently demonstrated that increases in S-glutathionylation promote pulmonary fibrosis, which was mitigated by the deglutathionylating enzyme glutaredoxin (GLRX). However, the protein targets of S-glutathionylation that promote fibrogenesis remain unknown. In the present study we addressed whether the extracellular matrix is a target for S-glutathionylation. We discovered increases in COL1A1 (collagen 1A1) S-glutathionylation (COL1A1-SSG) in lung tissues from subjects with IPF compared with control subjects in association with increases in ERO1A (endoplasmic reticulum [ER] oxidoreductin 1) and enhanced oxidation of ER-localized PRDX4 (peroxiredoxin 4), reflecting an increased oxidative environment of the ER. Human lung fibroblasts exposed to TGFB1 (transforming growth factor-β1) show increased secretion of COL1A1-SSG. Pharmacologic inhibition of ERO1A diminished the oxidation of PRDX4, attenuated COL1A1-SSG and total COL1A1 concentrations, and dampened fibroblast activation. Absence of enhanced COL1A1-SSG and overall COL1A1 secretion and promoted the activation of mechanosensing pathways. Remarkably, COL1A1-SSG resulted in marked resistance to collagenase degradation. Compared with COL1, lung fibroblasts plated on COL1-SSG proliferated more rapidly and increased the expression of genes encoding extracellular matrix crosslinking enzymes and genes linked to mechanosensing pathways. Overall, these findings suggest that glutathione-dependent oxidation of COL1A1 occurs in settings of IPF in association with enhanced ER oxidative stress and may promote fibrotic remodeling because of increased resistance to collagenase-mediated degradation and fibroblast activation.