Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration

Academic Article

Abstract

  • © 2020 Web Portal AAAS - American Association for the Advancement of Science. All rights reserved. The oxidation of tyrosine residues to generate o,o′-dityrosine cross-links in extracellular proteins is necessary for the proper function of the extracellular matrix (ECM) in various contexts in invertebrates. Tyrosine oxidation is also required for the biosynthesis of thyroid hormone in vertebrates, and there is evidence for oxidative cross-linking reactions occurring in extracellular proteins secreted by myofibroblasts. The ECM protein fibronectin circulates in the blood as a globular protein that dimerizes through disulfide bridges generated by cysteine oxidation. We found that cellular (fibrillar) fibronectin on the surface of transforming growth factor–β1 (TGF-β1)–activated human myofibroblasts underwent multimerization by o,o′-dityrosine cross-linking under reducing conditions that disrupt disulfide bridges, but soluble fibronectin did not. This reaction on tyrosine residues required both the TGF-β1–dependent production of hydrogen peroxide and the presence of myeloperoxidase (MPO) derived from inflammatory cells, which are active participants in wound healing and fibrogenic processes. Oxidative cross-linking of matrix fibronectin attenuated both epithelial and fibroblast migration and conferred resistance to proteolysis by multiple proteases. The abundance of circulating o,o′-dityrosine–modified fibronectin was increased in a murine model of lung fibrosis and in human subjects with interstitial lung disease compared to that in control healthy subjects. These studies indicate that tyrosine can undergo stable, covalent linkages in fibrillar fibronectin under inflammatory conditions and that this modification affects the migratory behavior of cells on such modified matrices, suggesting that this modification may play a role in both physiologic and pathophysiologic tissue repair.
  • Published In

  • Science Signaling  Journal
  • Digital Object Identifier (doi)

    Author List

  • Locy ML; Rangarajan S; Yang S; Johnson MR; Bernard K; Kurundkar A; Bone NB; Zmijewski JW; Byun J; Pennathur S
  • Volume

  • 13
  • Issue

  • 644