Phospho-NEDD4L (Ser342)

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

Full Name

Neural Precursor Cell Expressed, Developmentally Down-Regulated 4-Like, E3 Ubiquitin Protein Ligase

Function

E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair (PubMed:31959741, PubMed:33608556, PubMed:20064473).

Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation (PubMed:15496141).

Downregulates autophagy and cell growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels (PubMed:28820317, PubMed:31959741).

Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338).

Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).

Plays a role in dendrite formation by melanocytes (PubMed:23999003).

Involved in the regulation of TOR signaling (PubMed:27694961).

Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338).

Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and 'Lys-63'-linked ubiquitination of TRAF3 (PubMed:33608556).

Biological Process

Cell differentiation Source: UniProtKB-KW
Ion transmembrane transport Source: Reactome
Negative regulation of potassium ion transmembrane transport Source: BHF-UCL
Negative regulation of potassium ion transmembrane transporter activity Source: BHF-UCL
Negative regulation of protein localization to cell surface Source: BHF-UCL
Negative regulation of sodium ion transmembrane transport Source: BHF-UCL
Negative regulation of sodium ion transmembrane transporter activity Source: BHF-UCL
Positive regulation of caveolin-mediated endocytosis Source: BHF-UCL
Positive regulation of dendrite extension Source: UniProtKB
Positive regulation of protein catabolic process Source: GO_Central
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: BHF-UCL
Protein K48-linked ubiquitination Source: BHF-UCL
Protein polyubiquitination Source: GO_Central
Protein ubiquitination Source: UniProtKB
Regulation of dendrite morphogenesis Source: GO_Central
Regulation of ion transmembrane transport Source: BHF-UCL
Regulation of membrane depolarization Source: BHF-UCL
Regulation of membrane potential Source: BHF-UCL
Regulation of membrane repolarization Source: BHF-UCL
Regulation of potassium ion transmembrane transporter activity Source: BHF-UCL
Regulation of protein stability Source: UniProtKB
Regulation of sodium ion transmembrane transport Source: UniProtKB
Ubiquitin-dependent protein catabolic process Source: BHF-UCL
Ventricular cardiac muscle cell action potential Source: BHF-UCL

Cellular Location

Cytoplasm
Endosome
multivesicular body
Golgi apparatus
Note: May be recruited to exosomes by NDFIP1.

Involvement in disease

Periventricular nodular heterotopia 7 (PVNH7):
A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH7 is an autosomal dominant disease characterized by delayed psychomotor development, intellectual disability, and seizures in some patients. Additional features include cleft palate and toe syndactyly.

PTM

Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation.
Auto-ubiquitinated (PubMed:19343052). Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other's ubiquitination levels (PubMed:27445338).