NEDD4L
NEDD4 Like E3 Ubiquitin Protein Ligase
Gene Information Card
| Symbol | NEDD4L |
|---|---|
| Full Name | NEDD4 Like E3 Ubiquitin Protein Ligase |
| Gene Type | Protein coding |
| Chromosomal Location | 18q21.31 |
| NCBI Gene ID | 23327 ncbi.nlm.nih.gov/gene/23327 |
| Ensembl ID | ENSG00000149759 |
| UniProt ID | Q96PU5 |
| OMIM ID | 606384 |
| HGNC ID | 17646 |
| Aliases | NEDD4-2, NEDD4.2, hNEDD4-2 |
Description
NEDD4L (NEDD4 Like E3 Ubiquitin Protein Ligase) encodes a member of the NEDD4 family of HECT domain E3 ubiquitin ligases. The protein regulates the cell surface expression of various ion channels and transporters, including the epithelial sodium channel (ENaC), by targeting them for ubiquitination and endocytosis. NEDD4L plays critical roles in blood pressure regulation, neuronal development, and cellular signaling. Alternative splicing generates multiple isoforms with distinct regulatory properties.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hypertension, salt-sensitive | Loss-of-function variants reduce ENaC ubiquitination, leading to increased sodium reabsorption and elevated blood pressure | ClinVar, OMIM |
| Liddle syndrome (phenocopy) | Impaired NEDD4L-mediated ENaC downregulation mimics Liddle syndrome | OMIM #606384 |
| Epileptic encephalopathy, early infantile | De novo missense variants disrupt neuronal ion channel regulation | ClinVar, OMIM |
| Colorectal cancer | Altered NEDD4L expression affects TGF-β signaling and tumor suppression | COSMIC, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | 12.5 | Medium |
| Brain | 8.3 | Medium |
| Lung | 6.1 | Low |
| Heart | 4.7 | Low |
| Liver | 3.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 15.2 | High expression |
| SH-SY5Y | 10.8 | Medium expression |
| A549 | 7.4 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1615C>T (p.Arg539Cys) | Missense | <0.01% | Reduced ENaC ubiquitination; associated with hypertension |
| c.1942G>A (p.Gly648Arg) | Missense | <0.01% | De novo; linked to epileptic encephalopathy |
| c.2260_2262del (p.Lys754del) | In-frame deletion | <0.01% | Altered HECT domain activity |
Mutation functional classification
Loss of Function (LOF)
Reduced ubiquitin ligase activity toward ENaC and other substrates, leading to increased channel surface expression and salt-sensitive hypertension.
Gain of Function (GOF)
Not well characterized; some variants may enhance degradation of tumor suppressors.
Dominant Negative (DN)
Possible for certain missense mutations that interfere with wild-type NEDD4L function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Ubiquitin mediated proteolysis (KEGG hsa04120)
• Endocytosis (KEGG hsa04144)
• Aldosterone-regulated sodium reabsorption (KEGG hsa04960)
• TGF-beta signaling pathway (Reactome R-HSA-170834)
Protein Summary
NEDD4L is a 975-amino acid HECT domain E3 ubiquitin ligase. It contains an N-terminal C2 domain, four WW domains that mediate substrate recognition, and a C-terminal HECT domain responsible for ubiquitin transfer. The protein ubiquitinates membrane proteins such as ENaC, TGF-β receptor, and voltage-gated sodium channels, targeting them for endocytosis and lysosomal degradation. NEDD4L activity is regulated by phosphorylation, autoinhibition, and interaction with NDFIP proteins. Isoform diversity arises from alternative splicing of exons encoding the WW domains.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NEDD4L Knockout HEK293 Cell Line | EDJ-KQ3107 | Human | 23327 | Details Get a Quote |
| NEDD4L Knockout A-549 Cell Line | EDJ-KQ24440 | Human | 23327 | Details Get a Quote |
| NEDD4L Knockout HCT 116 Cell Line | EDJ-KQ24441 | Human | 23327 | Details Get a Quote |
| NEDD4L Knockout HeLa Cell Line | EDJ-KQ24442 | Human | 23327 | Details Get a Quote |
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