NEDD4L

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]
Diseases associated with NEDD4L include Periventricular Nodular Heterotopia 7 and Periventricular Nodular Heterotopia. Among its related pathways are Gene expression (Transcription) and HIV Life Cycle. Gene Ontology (GO) annotations related to this gene include ligase activity and transmembrane transporter binding. An important paralog of this gene is NEDD4.
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:20064473, 31959741, 33608556).
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, 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, 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).
Ubiquitinates TTYH2 and TTYH3 and regulates protein levels of TTYH2 (PubMed:18577513).
Induction:
By androgens in prostate, and by albumin in kidney.
Activated by NDFIP1- and NDFIP2-binding.
neural precursor cell expressed gene 4-like,developmentally down-regulated 4-like
Cytoplasm {ECO:0000269 PubMed:15496141, 18819914, 27694961}
Golgi apparatus {ECO:0000269 PubMed:26363003}
Endosome, multivesicular body {ECO:0000269 PubMed:26363003}
Note: May be recruited to exosomes by NDFIP1.
Quaternary structure:
Interacts with UBE2E3 (By similarity).
Interacts with NDFIP1; this interaction activates the E3 ubiquitin-protein ligase (PubMed:11748237, 26363003).
Interacts with NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:26363003).
Interacts (via WW domains) with SCNN1A (PubMed:11244092, 11696533, 14556380).
Interacts (via WW domains) with SCNN1B (PubMed:11244092, 14556380).
Interacts (via WW domains) with SCNN1G (PubMed:11244092, 14556380).
Interacts (via WW domains) with SCN1A (By similarity).
Interacts (via WW domains) with SCN2A (PubMed:15548568).
Interacts (via WW domains) with SCN3A (PubMed:15548568).
Interacts (via WW domains) with SCN5A (PubMed:15217910, 15548568).
Interacts (via WW domains) with SCN8A (By similarity).
Interacts (via WW domains) with SCN9A (By similarity).
Interacts (via WW domains) with SCN10A (By similarity).
Interacts (via WW domains) with CLCN5 (PubMed:15489223).
Interacts with SMAD2 (PubMed:15496141).
Interacts with SMAD3 (PubMed:15496141).
Interacts with SMAD6 (PubMed:15496141).
Interacts with SMAD7 (PubMed:15496141).
The phosphorylated form interacts with 14-3-3 proteins (PubMed:15677482).
Interacts with TNK2 (PubMed:19144635, 20086093).
Interacts with WNK1 (PubMed:20525693).
Interacts with SGK1 (PubMed:11696533, 20730100).
Interacts (via C2 domain) with NPC2 (PubMed:19664597).
Interacts with ARRDC4 (PubMed:23236378).
Interacts with KCNQ1; promotes internalization of KCNQ1 (PubMed:22024150).
Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338).
Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930).
Interacts with LDLRAD3; the interaction is direct (PubMed:26854353).
Interacts with UBE2D2 (PubMed:20064473).
Interacts with TTYH2 and TTYH3 (PubMed:18577513).