Anaerobic Transcription by OxyR: A Novel Paradigm for Nitrosative Stress

Significance: S-nitrosylation, the post-translational modification by nitric oxide (NO) to form S-nitrosothiols (SNOs), regulates diverse aspects of cellular function, and aberrant S-nitrosylation (nitrosative stress) is implicated in disease, from neurodegeneration to cancer. Essential roles for S-nitrosylation have been demonstrated in microbes, plants, and animals; notably, bacteria have often served as model systems for elucidation of general principles. 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.