E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) is an enzyme responsible for transferring ubiquitin to substrate proteins, targeting them for proteasomal degradation or modulating their cellular localization and function[2][3]. NEDD4L is a member of the HECT-type E3 ubiquitin ligase family and consists of a modular architecture: an N-terminal C2 domain (membrane binding, calcium-dependent), multiple WW domains (protein-protein interaction, substrate recognition) and a C-terminal HECT domain (catalytic ubiquitin transfer)[2][3][4]. NEDD4L plays a key role in regulating membrane proteins such as the epithelial sodium channel (ENaC), Na+-Cl- co-transporter (NCC), and various voltage-gated sodium channels, and can also modulate signaling pathways such as EGFR, TGFβ and WNT[2][3]. By influencing salt excretion in the kidneys, it opposes aldosterone and is critical in blood pressure regulation; loss-of-function mutations are associated with Liddle's syndrome and hypertension[2]. NEDD4L also regulates viral protein turnover, DNA damage response, cell cycle, apoptosis, differentiation, and innate immune responses[1][4]. Its catalytic activity is tightly regulated by intra-molecular interactions (autoinhibition), phosphorylation, and interaction with accessory proteins such as 14-3-3[3]. NEDD4L is widely expressed, with varying isoforms predominant in kidney, adrenal gland, and lung[2]. It is considered both a potential tumor suppressor and, in some contexts, oncogenic depending on substrate specificity, cellular context, and regulation[6]. Because of its multifaceted roles in disease, NEDD4L is actively studied as a therapeutic target and biomarker, but no specific drugs have reached clinical use targeting it directly[5].

Other names

NEDD4LNEDD4-2Neural precursor cell expressed, developmentally down-regulated 4-likeKIAA0439NEDL3RSP5NEDD4.2Nedd4-2PVNH7hNEDD4-2ubiquitin-protein ligase Rsp5

Inhibiting NEDD4L could block ubiquitination and stabilize target proteins (e.g. ENaC). Activating NEDD4L could enhance substrate degradation (mainly experimental).