Oxidative stress is a result of imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense systems, leading to cellular damage. It has been found to be associated with the initiation and progression of a variety of human diseases. In many types of cells, oxidative stress has been shown to drive the S-glutathionylation of free thiol groups (-SH) on the cysteine residues of proteins to form protein-glutathione mixed disulfide adducts (Pr-SSG). Protein S-glutathionylation is a dynamic reversible process and regulates the structure and function of target proteins. De-glutathionylation is mainly catalyzed by glutaredoxin (Grx), a thiol disulfide oxido-reductase (thioltransferase).
In recent years, the research team led by associate Prof. ZHANG Xue /Prof. KE Yuehai from Zhejiang University School of Medicine has conducted systematic research into protein post-translational modification. The latest research results were published in the journal Nature Communications on December 07, and entitled “Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages”.
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. Researchers report that the expression of deglutathionylation enzyme Grx1 is decreased in the lungs of acute lung injury mice. The acute lung injury induced by hyperoxia or LPS is significantly relieved in Grx1 KO and Grx1fl/flLysMcre mice, confirming the protective role of Grx1-regulated S-glutathionylation in macrophages. Using a quantitative redox proteomics approach, researchers show that FABP5 is susceptible to S-glutathionylation under oxidative conditions. S-glutathionylation of Cys127 in FABP5 promotes its fatty acid binding ability and nuclear translocation. Further results indicate S-glutathionylation promotes the interaction of FABP5 and PPARβ/δ, activates PPARβ/δ target genes and suppresses the LPS-induced inflammation in macrophages. Our study reveals a molecular mechanism through which FABP5 S-glutathionylation regulates macrophage inflammation in the pathogenesis of acute lung injury.
