Positive Regulation of Interleukin-1 Beta Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation

Abstract

Reactive oxygen species (ROS)‐induced Cysteine S‐glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S‐glutathionylation remains elusive. Here using a screening approach, we identified ROS‐mediated cysteine S‐glutathionylation on several extracellular cytokines. Glutathionylation positively regulated IL‐1β bioactivity via the highly conserved Cys‐188 residue by preventing its ROS‐induced irreversible oxidation, including sulfinic acid and sulfonic acid formation, and the subsequent deactivation ex vivo and in an in vivo system of irradiation‐induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL‐1β glutathionylation and bioactivity. Collectively, we identify cysteine S‐glutathionylation as a novel cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.