The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the master regulator of the cellular cytoprotective responses, controlling the expression of nearly 2% of the human genome. The Nrf2 regulatory network is at the interface between redox and intermediary metabolism (Hayes and Dinkova-Kostova, 2014), and plays a critical role in the resolution of inflammation (Mills et al. 2018). Together with its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (Keap1), the transcriptional activity of Nrf2 affects the development and progression of cancer, chronic diseases of the lung and liver, as well as autoimmunity, neurodegenerative and metabolic diseases. Thus, the activation of Nrf2 provides protection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances, whereas Nrf2 dysregulation is causally associated with the development of chronic disease.
We have previously shown that, at homeostatic conditions Keap1 uses a cyclical mechanism to target Nrf2 for ubiquitination and proteasomal degradation (Baird et al. 2013). The cycle is disrupted in response to small molecules (termed inducers) as well as protein regulators, such as the autophagy cargo protein p62, leading to Nrf2 accumulation and transcription of genes encoding cytoprotective enzymes. This project will employ live cell imaging combined with mathematical modelling to define the spatiotemporal control of the conformational cycling of the Keap1 : Nrf2 protein complex, testing the hypothesis that such cycling allows cross-regulation of multiple signalling pathways. It will bring comprehensive understanding of the mechanisms controlling Nrf2 function, suggesting new strategies for disease prevention and treatment.
The project will provide research training in cellular and molecular biology, live cell imaging, and mathematical modelling of protein-protein interactions that regulate fundamental biological processes.
Baird L et al. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci USA 2013; 110: 15259-64.
Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014; 39: 199-218.
Mills et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 2018; 556: 113-117.