Cell Reports
Volume 20, Issue 1, 5 July 2017, Pages 224-235
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Article
Positive Regulation of Interleukin-1β Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation

https://doi.org/10.1016/j.celrep.2017.05.070Get rights and content
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Highlights

  • The most conserved cysteine in mature IL-1β, Cys-188, can be S-glutathionylated

  • Cysteine S-glutathionylation protects IL-1β from H2O2-induced deactivation

  • S-glutathionylation of Cys188 is required for maintaining IL-1β bioactivity in vivo

  • Grx1 is a physiological negative regulator of IL-1β cysteine S-glutathionylation

Summary

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 is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1β from deactivation by ROS 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 cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.

Keywords

cytokines
interleukin-1
oxidation
infection and inflammation
reactive oxygen species
posttranslational modification
cysteine S-glutathionylation

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These authors contributed equally

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