Glutathionylation of fibronectin records mechanical history, priming an integrin switch and myofibroblast polarization

Abstract The extracellular matrix (ECM) is a protein polymer network that physically supports cells within a tissue and also acts as an important biochemical stimulus directing cell behaviors. For fibronectin, a predominant component of the ECM, these physical and biochemical activities are inextricably linked as physical forces trigger conformational changes that impact its biochemical activity. We analyzed whether oxidative post-translational modifications, specifically glutathionylation, enable fibronectin to ‘record’ physical information through stretch-dependent protein modification. Posttranslational modifications of the ECM are understudied, but represent opportunities for time- or stimuli-dependent changes in structure-function relationships that both persist over time and could have dominant impacts on cell-ECM homeostasis. We provide direct evidence that stretch-dependent glutathionylation of fibronectin irreversibly and significantly alters its mechanical properties with concomitant changes in the binding of integrin receptors and downstream cell signaling events. Stretch-dependent glutathionylation of fibronectin could have significant impact on the balance between tissue homeostasis and pathological progression, particularly in tissues and organs that are exposed to high oxidative stress, such as the lung.