The winners of the 2019 Nobel Prize in Physiology or Medicine were announced here in Stockholm last week. William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza were jointly awarded for their discoveries of how cells sense and adapt to oxygen availability.

Oxygen is essential for the metabolism for almost all animals. It is used by mitochondria in the aerobic respiration for the generation of ATP and thereby providing energy to the cell. The amount of available oxygen has an effect on the cellular metabolism and hence it is important for cells to adapt to different oxygen levels. Kaelin, Ratcliffe and Semenza identified the proteins and mechanisms that are involved in this adaption process. The main player is a complex named hypoxia-inducible factor (HIF), which consists of the two transcription factors, HIF-1a and ARNT (Wang et al, 1995). At low oxygen levels (hypoxia), the HIF complex regulates gene expression in the nucleus and increases for example the expression of genes involved in glycolysis to maintain the cellular ATP level.

At high oxygen levels ("normoxia"), the cells contain only little HIF-1a. It was Kaelin who could show that the interaction of HIF-1a with another protein, von Hippel-Lindau disease tumor suppressor (VHL), leads to a rapid proteasomal degradation of HIF-1a in the cytosol (Maxwell et al, 1999). The interaction is mediated by a post-translational modification of HIF-1a called prolyl hydroxylation, which is necessary for VHL to recognize and bind to HIF-1a (Ivan et al, 2001, Jaakkola et al, 2001). Theis post-translational modification is made by oxygen-sensitive prolyl hydroxylases, which are the cellular sensors for the oxygen level. In the HPA Cell Atlas, we cultivate our cell lines under atmospheric/normoxic oxygen conditions. Therefore, the cells have a high activity of prolyl hydroxylases, for example HIF-PH3 encoded by the EGLN3 gene. It is localizing to the cytosol where it hydroxylates HIF-1a targeting it for degradation in the proteasome.

Peter Thul