New horizons in hypoxia signalling

Oxygen homeostasis is central to most forms of life and its breakdown complicates most human diseases. Although regulation of the HIF transcriptional cascade by oxygen-dependent prolyl hydroxylation (HIF/PHD system) has provided important insights, it cannot, alone, deliver the precision implicit in physiological oxygen homeostasis, particularly rapid responses that are inconsistent with dependence on new transcription. We will define the physiological role of a new system of human oxygen sensing, recently identified in this laboratory, which directly regulates signalling intermediates by N-Cys dioxygenation coupled to N-degron mediated proteolysis, an oxygen sensitive reaction catalysed by cysteamine (2-aminoethanethiol) dioxygenase (ADO). We will define the range of substrates of ADO and their role in the physiology of oxygen homeostasis. We will determine how the HIF/PHD and ADO/N-Cys systems interact, including their interactions with oxygen chemoreceptor mechanisms that transduce rapid electrophysiological responses to hypoxia in excitable cells. The work aims to provide new insights into the mechanism(s) of chemosensitivity and new systems for its study. Our aim is to deliver new paradigms in the understanding of hypoxia signalling, which will have broad relevance to medical physiology, offer new entry points for medicine discovery and deliver new resources to the research community.