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

Overview

Journal Am J Respir Cell Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2024 Jul 23

PMID 39042020

Authors

Joseph E Druso

Maximilian B MacPherson

Shi B Chia

Evan Elko

Reem Aboushousha

David J Seward

Hend Abdelhamid

Cuixia Erickson

Elizabeth Corteselli

Megan Tarte

Zhihua Peng

Daniel Bernier

Ester Zito

Matthew D Shoulders

Victor J Thannickal

Steven Huang

Albert van der Vliet

Vikas Anathy

Yvonne M W Janssen-Heininger

Affiliations

Soon will be listed here.

Abstract

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.

References

He J, Becares E, Thulstrup P, Gamon L, Pedersen J, Otzen D . Peroxynitrous acid (ONOOH) modifies the structure of anastellin and influences its capacity to polymerize fibronectin. Redox Biol. 2020; 36:101631. PMC: 7364157. DOI: 10.1016/j.redox.2020.101631. View

Wei Y, Dong W, Jackson J, Ho T, Jourdan Le Saux C, Brumwell A . Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021; 76(7):729-732. PMC: 8222054. DOI: 10.1136/thoraxjnl-2020-215745. View

Martinez F, Collard H, Pardo A, Raghu G, Richeldi L, Selman M . Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017; 3:17074. DOI: 10.1038/nrdp.2017.74. View

Locy M, Rangarajan S, Yang S, Johnson M, Bernard K, Kurundkar A . Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration. Sci Signal. 2020; 13(644). PMC: 9394744. DOI: 10.1126/scisignal.aau2803. View

Jones M, Andriotis O, Roberts J, Lunn K, Tear V, Cao L . Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. Elife. 2018; 7. PMC: 6029847. DOI: 10.7554/eLife.36354. View

Swiatkowska M, Szymanski J, Padula G, Cierniewski C . Interaction and functional association of protein disulfide isomerase with alphaVbeta3 integrin on endothelial cells. FEBS J. 2008; 275(8):1813-23. DOI: 10.1111/j.1742-4658.2008.06339.x. View

Mor-Cohen R . Disulfide Bonds as Regulators of Integrin Function in Thrombosis and Hemostasis. Antioxid Redox Signal. 2014; 24(1):16-31. DOI: 10.1089/ars.2014.6149. View

Mierke C, Fischer T, Puder S, Kunschmann T, Soetje B, Ziegler W . Focal adhesion kinase activity is required for actomyosin contractility-based invasion of cells into dense 3D matrices. Sci Rep. 2017; 7:42780. PMC: 5311912. DOI: 10.1038/srep42780. View

Martinez F, de Andrade J, Anstrom K, King Jr T, Raghu G . Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2093-101. PMC: 4116664. DOI: 10.1056/NEJMoa1401739. View

10.

McMillan D, van der Velden J, Lahue K, Qian X, Schneider R, Iberg M . Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione--transferase π. JCI Insight. 2016; 1(8). PMC: 4922427. DOI: 10.1172/jci.insight.85717. View

11.

Elko E, Cunniff B, Seward D, Chia S, Aboushousha R, van de Wetering C . Peroxiredoxins and Beyond; Redox Systems Regulating Lung Physiology and Disease. Antioxid Redox Signal. 2019; 31(14):1070-1091. PMC: 6767868. DOI: 10.1089/ars.2019.7752. View

12.

Jin X, Stamnaes J, Klock C, Diraimondo T, Sollid L, Khosla C . Activation of extracellular transglutaminase 2 by thioredoxin. J Biol Chem. 2011; 286(43):37866-73. PMC: 3199528. DOI: 10.1074/jbc.M111.287490. View

13.

Chen H, Qu J, Huang X, Kurundkar A, Zhu L, Yang N . Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis. Nat Commun. 2016; 7:12564. PMC: 4992155. DOI: 10.1038/ncomms12564. View

14.

Fiore V, Wong S, Tran C, Tan C, Xu W, Sulchek T . αvβ3 Integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis. JCI Insight. 2018; 3(20). PMC: 6237458. DOI: 10.1172/jci.insight.97597. View

15.

Zito E, Hansen H, Yeo G, Fujii J, Ron D . Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice. Mol Cell. 2012; 48(1):39-51. PMC: 3473360. DOI: 10.1016/j.molcel.2012.08.010. View

16.

Cantin A, North S, Hubbard R, Crystal R . Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985). 1987; 63(1):152-7. DOI: 10.1152/jappl.1987.63.1.152. View

17.

Wong M, Shoulders M . Targeting defective proteostasis in the collagenopathies. Curr Opin Chem Biol. 2019; 50:80-88. PMC: 6588406. DOI: 10.1016/j.cbpa.2019.02.021. View

18.

Pehrsson M, Mortensen J, Manon-Jensen T, Bay-Jensen A, Karsdal M, Davies M . Enzymatic cross-linking of collagens in organ fibrosis - resolution and assessment. Expert Rev Mol Diagn. 2021; 21(10):1049-1064. DOI: 10.1080/14737159.2021.1962711. View

19.

Yi M, Melkonian A, Ousey J, Khosla C . Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2. J Biol Chem. 2018; 293(8):2640-2649. PMC: 5827427. DOI: 10.1074/jbc.RA117.001382. View

20.

Ilani T, Alon A, Grossman I, Horowitz B, Kartvelishvily E, Cohen S . A secreted disulfide catalyst controls extracellular matrix composition and function. Science. 2013; 341(6141):74-6. DOI: 10.1126/science.1238279. View