Anaerobic Transcription by OxyR: A Novel Paradigm for Nitrosative Stress

Recent Advances: Recent conceptual advances include the idea of a molecular code through which proteins sense and differentiate S-nitrosothiol (SNO) from alternative oxidative modifications, providing the basis for specificity in SNO signaling. In Escherichia coli, S-nitrosylation relies on an enzymatic cascade that regulates, and is regulated by, the transcription factor OxyR under anaerobic conditions. S-nitrosylated OxyR activates an anaerobic regulon of >100 genes that encode for enzymes that both mediate S-nitrosylation and protect against nitrosative stress. Critical Issues: Mitochondria originated from endosymbiotic bacteria and generate NO under hypoxic conditions, analogous to conditions in E. coli. Nitrosative stress in mitochondria has been implicated in Alzheimer's and Parkinson's disease, among others. Many proteins that are S-nitrosylated in mitochondria are also S-nitrosylated in E. coli. Insights into enzymatic regulation of S-nitrosylation in E. coli may inform the identification of disease-relevant regulatory machinery in mammalian systems. Future Directions: Using E. coli as a model system, in-depth analysis of the anaerobic response controlled by OxyR may lead to the identification of enzymatic mechanisms regulating S-nitrosylation in particular, and hypoxic signaling more generally, providing novel insights into analogous mechanisms in mammalian cells and within dysfunctional mitochondria that characterize neurodegenerative diseases.