Glutaredoxin Desensitizes Lens to Oxidative Stress by Connecting and Integrating Specific Signaling and Transcriptional Regulation for Antioxidant Response.

BACKGROUND/AIMS: Oxidative stress plays a critical role in the development of cataracts, and glutaredoxins (Grxs) play a major protective role against oxidative stress in the lens. This study aimed to reveal the global regulatory network of Grx1. METHODS: Stable isotope labeling by amino acids in cell culture (SILAC) was used in a proteome-wide quantitative approach to identify the Grx1 regulatory signaling cascades at a subcellular resolution in response to oxidative stress. RESULTS: A total of 1,291 proteins were identified to be differentially expressed, which were further categorized into a variety of signaling cascades including redox regulation, apoptosis, cell cycle control, glucose metabolism, protein synthesis, DNA damage response, protein folding, proteasome and others. Thirteen key signaling node molecules representing each pathway were verified. Notably, the subunits of proteasome complexes, which play a pivotal role in preventing cytotoxicity via the degradation of oxidized proteins, were highly enriched by Grx1. By data-dependent network analysis, we found global functional links among these signaling pathways which elucidate how Grx1 integrates the operation of these regulatory networks in an interconnected way for H2O2-induced response. CONCLUSION: Our data provide a system-wide insight into the function of Grx1 and provide a basis for further mechanistic investigation of Grx1 in antioxidant responses in the lens.