The epithelial Na⁺ channel ENaC is critical for Na⁺ homeostasis and blood pressure regulation. It is controlled by a number of different regulatory systems, including ubiquitylation by Nedd4–2 modulating ENaC cell surface expression and cleavage of extracellular loops by luminal serine proteases activating ENaC. Ubiquitylation of ENaC is reversible and involves the aldosterone-induced deubiquitylating enzyme Usp2- 45. We have found recently that the two processes are related to each other, despite being topologically separated (i.e. cleavage at the luminal, deubiquitylation at the cytosolic side of the membrane). In my presentation I will present novel data that suggest possible mechanisms on how ubiquitylation of ENaC can influence the proteolytic stage of ENaC, and discuss functional and physiological consequences of such mechanisms.