Journal
CELL REPORTS
Volume 20, Issue 1, Pages 224-235Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.070
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Funding
- National Basic Research Program of China [2015CB964903]
- CAMS Innovation Fund for Medical Sciences [2016-12M-1-003]
- Chinese National Natural Science Foundation [31471116, 81600083]
- PUMC Youth Fund [3332015184]
- NIH [R01AI103142, R01HL092020, P01 HL095489]
- FAMRI [CIA130004]
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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-1 beta positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1b 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-1b 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.
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