Integrin-mediated cell adhesion requires extracellular disulfide exchange regulated by protein disulfide isomerase

• Published in: Experimental cell research Vol. 381; no. 1; pp. 77 - 85
• Main Authors: Rosenberg, Nurit, Mor-Cohen, Ronit, Sheptovitsky, Vera Hazan, Romanenco, Olga, Hess, Oded, Lahav, Judith
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2019
• Subjects: Cell adhesion; Collagen; Disulfide exchange; Fibronectin; Integrin; PDI; Disulfide exchange; Integrin; PDI; Collagen; Fibronectin; Cell adhesion
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2019.04.017

Cell adhesion to extracellular matrix, mediated by integrin receptors, is crucial for cell survival. Receptor-ligand interaction involves conformational changes in the integrin by a mechanism not fully elucidated. In addition to several direct evidence that there is disulfide re-arrangement of integrins, we previously demonstrated a role for extracellular thiols and protein disulfide isomerase (PDI) in integrin-mediated functions using platelets as model system. Exploring the possible generality of this mechanism, we now show, using three different nucleated cells which depend on adhesion for survival, that non-penetrating blockers of free thiols inhibit α2β1 and α5β1 integrin-mediated adhesion and that disulfide exchange takes place in that process. Inhibiting extracellular PDI mimics thiol blocking. Transfection with WT or enzymatically inactive PDI increased their membrane expression and enhanced cell adhesion, suggesting that PDI level is a limiting factor and that the chaperone activity of the enzyme contributes to adhesion. Exogenously added PDI also enhanced adhesion, further supporting the limiting factor of the enzyme. These data indicate that: a) Dependence on ecto-sulfhydryls for integrin-mediated adhesion is not exclusive to the platelet; b) PDI is involved in integrin-mediated adhesion, catalyzing disulfide bond exchange; c) PDI enhances cell adhesion by both its oxidoreductase activity and as a chaperone. •Disulfide exchange is required for integrin-mediated adhesion of nucleated cells.•Protein disulfide isomerase (PDI) mediates disulfide exchange during cell adhesion.•The level of membrane associated PDI is a limiting factor for adhesion.•Both oxidoreductase and chaperone activity of PDI are involved in adhesion.