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

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Xue Zhang, Peng Liu, Christie Zhang, Direkrit Chiewchengchol, Fan Zhao, Hongbo Yu, Jingyu Li, Hiroto Kambara, Kate Y. Luo, Arvind Venkataraman, Ziling Zhou, Weidong Zhou, Haiyan Zhu, Li Zhao, Jiro Sakai, Yuanyuan Chen, Ye-Shih Ho, Besnik Bajrami, Bing Xu, Leslie E. Silberstein, Tao Cheng, Yuanfu Xu, Yuehai Ke, Hongbo R. Luo
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.

Graphical abstract

Teaser

Zhang et al. reveal that cysteine S-glutathionylation of the highly conserved Cys-188 residue of IL-1β positively regulates its bioactivity by preventing its irreversible ROS-elicited deactivation. ROS-induced cysteine glutathionylation and its modulation by Glutaredoxin 1 (Grx1) are key physiological regulatory mechanisms controlling IL-1β activity, providing a potential therapeutic target in the treatment of infectious and inflammatory diseases.


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