期刊
ANTIOXIDANTS
卷 9, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/antiox9030227
关键词
redox regulation; redox signaling; integrin alpha 7 beta 1; thiol-switch; extracellular thioredoxin-1; laminin binding; cell migration
资金
- Deutsche Forschungsgemeinschaft (DFG) [Eb177/14-1, Ha 8334/2-2, SPP1710, SFB1009]
- Medical Faculty of the University of Munster within the IZKF program (IZKF) [Ebl2/014/16]
While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of alpha 7 beta 1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the alpha-subunit hinge region was replaced for alanines. The molecular and cellular effects were analyzed by electron and atomic force microscopy, impedance-based migration assays, flow cytometry and live cell imaging. This cysteine pair constitutes a thiol-switch, which redox-dependently governs the equilibrium between an extended and a bent integrin conformation with high and low ligand binding activity, respectively. Hydrogen peroxide oxidizes the cysteines to a disulfide bond, increases ligand binding and promotes cell migration toward laminin-111. Inversely, extracellular thioredoxin-1 reduces the disulfide, thereby decreasing laminin binding. Mutation of this cysteine pair into the non-oxidizable hinge-mutant shows molecular and cellular effects similar to the reduced wild-type integrin, but lacks redox regulation. This proves the existence of a dominant thiol-switch within the alpha subunit hinge of alpha 7 beta 1 integrin, which is sufficient to implement activity regulation by extracellular redox agents in a redox-regulatory circuit. Our data reveal a novel and physiologically relevant thiol-based regulatory mechanism of integrin-mediated cell-ECM interactions, which employs short-lived hydrogen peroxide and extracellular thioredoxin-1 as signaling mediators.
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