Extracellular Matrix and Redox Signaling in Cellular Responses to Stress

Abstract

Cells in multicellular organisms communicate extensively with neighboring cells and distant organs using a variety of secreted proteins and small molecules. Cells also reside in a structural extracellular matrix (ECM), and changes in its composition, mechanical properties, and post-translational modifications provide additional layers of communication. This Forum addresses emerging mechanisms by which redox signaling controls and is controlled by changes in the ECM, focusing on the roles of matricellular proteins. These proteins engage specific cell surface signaling receptors, integrins, and proteoglycans to regulate the biosynthesis and catabolism of redox signaling molecules and the activation of their signal transducers. These signaling pathways, in turn, regulate the composition of ECM and its function. Covalent post-translational modifications of ECM by redox molecules further regulate its structure and function. Recent studies of acute injuries and chronic disease have identified important pathophysiological roles for this cross-talk and new therapeutic opportunities. Antioxid. Redox Signal. 27, 771-773.

Keywords: extracellular matrix; hydrogen sulfide; hypoxia; matricellular proteins; nitric oxide; reactive oxygen species.

FIG. 1.

Bidirectional cross-talk between ECM and redox signaling. A subset of structural proteins in the ECM and dynamically regulated matricellular proteins engage specific cell surface receptors that regulate the biosynthesis and catabolism of redox signaling molecules produced by nitric oxide synthases (NOSs), NADPH oxidases (NOXs), lipoxygenases (LOX), and the H₂S biosynthetic enzymes cystathionine β-synthase and cystathionine γ-lyase. The matricellular protein thrombospondin-1 also regulates signal transduction downstream of NO. Redox signal transducers, in turn, regulate matricellular and ECM protein expression, degradation, and post-translational modifications, including the peroxidasin-mediated sulfilimine cross-linking of type IV collagen (C-IV) in basement membranes. Hypoxia regulates ECM protein expression by altering cellular redox chemistry that regulates multiple targets, including the hypoxia-induced transcription factors. ECM, extracellular matrix.