AMP(K)lifying Nrf2 target gene expression

Our cells are constantly exposed to multiple stress factors and potential hazards for proper cell function, e.g. in form of reactive oxygen species, misfolded proteins or inadequate supply with nutrients. In order to cope with these insults and to ensure vital homeostasis, they have developed specific programs to fight and adapt to the different stress situations. Two important hubs in this cell protection system are Nrf2, a redox-sensitive transcription factor, that mediates induction of antioxidant genes, and AMPK, a kinase activated by low energy status and favoring energy production but hindering energy consumption. This project builds on previous data that have shown that Nrf2 and AMPK crosstalk with each other: activation of AMPK (i.e. the lack of energy) signals to the redox sensor Nrf2 and controls the extent to which specific Nrf2-dependent protective genes are expressed. We now want to answer how this communication is achieved on the molecular level. Tackled questions comprise among others: a) Is AMPK signalling to Nrf2 by directly attaching a phosphate group to the transcription factor? b) How can such a phosphorylation of Nrf2 lead to an altered activity, and why does it differently affect distinct sets of Nrf2-target genes? c) Does AMPK also affect the chromatin landscape around Nrf2 target genes, e. g. the accessibility of genetic information for the transcription machinery or the nature of recruited activating or repressing proteins? The project will provide deeper insight into the emerging crosstalk between different cellular stress response programs, in particular how the cellular energy homeostasis can influence the protection from redox stress. This knowledge will unravel fundamental contexts in cell biology. It may also offer new inspiration for the development of drugs (dual Nrf2 and AMPK activators) or rational dietary regimens (with AMPK and Nrf2 signalling being activated by a plethora of food derived compounds) for a healthier aging and the prevention of chronic diseases which notably are characterized by a decline of the cellular stress resilience.