The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels

Most organisms have developed strategies to survive in low oxygen environments. Central to this response are proteins called Hypoxia Inducible Factors (HIFs), which activate genes involved in energy production and blood vessel growth when oxygen is scarce. When plenty of oxygen is present, HIFs are rapidly broken down. This is important because HIFs have also been linked to the growth and spread of cancers. Oxygen sensing enzymes, termed prolyl hydroxylases, play a principal role in controlling the break down of HIFs when oxygen is abundant. However, the activity of these prolyl hydroxylases can be reduced by changes in the nutrient or iron levels present in the cell. This raises questions about how other cell mechanisms help to control HIF levels. By using a technique called an unbiased forward genetic screen to study human cells, Miles, Burr et al. set out to identify the cellular pathways that regulate HIF levels when oxygen is still abundant. Disrupting a pump called the V-ATPase – which normally helps to break down unwanted proteins by acidifying the cellular compartments where they are destroyed – stabilised HIFs. Moreover, Miles, Burr et al. identified two previously uncharacterised genes that are required for the V-ATPase to work correctly. While the V-ATPase is typically associated with the destruction of proteins, a different, unexpected aspect of its activity is responsible for stabilising HIFs. Blocking activity of the V-ATPase reduces levels of iron inside the cell. This inhibits the activity of the prolyl hydroxylases, resulting in HIFs being activated. Overall, the findings presented by Miles, Burr et al. show key links between oxygen sensing, the use of iron and the V-ATPase. Further work is now needed to investigate how V-ATPase activity affects levels of HIFs found inside cells during diseases such as cancer.