Figure 6.

Potential regulation of AQP2 by USP4. Natively folded AQP2 traffics to the Golgi apparatus, is organized into tetramers, and stored in transport vesicles. Following vasopressin (VP) stimulation of the V2R, AQP2 traffics to the plasma membrane (PM) and is phosphorylated at Ser/Thr269, which stimulates AQP2 interaction with USP4. This interaction limits the degree of AQP2 ubiquitylation and allows AQP2 to accumulate on the plasma membrane. Alternatively, following AQP2 internalization, USP4 activity determines whether AQP2 is deubiquitylated and recycled to the PM, or targeted for lysosomal degradation. A number of collecting duct specific E3 ligases may be involved in these processes. Note, the relationship of ubiquitylation and phosphorylation of AQP2 within a tetramer is unknown and the figure does not aim to depict a specific stoichiometry.