Elevated intracellular Na⁺ and osmolarity stimulate catalytic activity of the ubiquitin ligase Nedd4-2.

ABSTRACT: Regulation of catalytic activity of E3 ubiquitin ligases is critical for their cellular functions. We identified an unexpected mode of regulation of E3 catalytic activity by ions and osmolarity; enzymatic activity of the HECT family E3 Nedd4-2/Nedd4L is enhanced by increased intracellular Na⁺ ([Na⁺]_i) and by hyperosmolarity. This stimulated activity is mediated by activation of p38-MAPK and is inhibited by WNKs. Moreover, protease (Furin)-mediated activation of the epithelial Na⁺ channel ENaC (a bona fide Nedd4-2 substrate), which leads to increased [Na⁺]_i and osmolarity, results in enhanced Nedd4-2 catalytic activity. This enhancement is inhibited by a Furin inhibitor, by a protease-resistant ENaC mutant, or by treatment wi

SUBMITTER: Persaud A 

PROVIDER: S-EPMC9335340 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature