NAE1 (NEDD8 Activating Enzyme E1 Subunit 1)
A key regulator of neddylation, essential for cullin-RING ubiquitin ligase (CRL) activity and cellular homeostasis.
Gene Information Card
| Symbol | NAE1 |
|---|---|
| Full Name | NEDD8 activating enzyme E1 subunit 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 16q22.1 |
| NCBI Gene ID | 8883 ncbi.nlm.nih.gov/gene/8883 |
| Ensembl ID | ENSG00000103168 |
| UniProt ID | Q13564 |
| OMIM ID | 603385 |
| HGNC ID | 764 |
| Aliases | APPBP1, NEDD8-activating enzyme E1 regulatory subunit, hNAE1 |
Description
NAE1 encodes the regulatory subunit of the NEDD8-activating enzyme (NAE), a heterodimer composed of NAE1 and UBA3. NAE catalyzes the first step in neddylation, the conjugation of the ubiquitin-like protein NEDD8 to target proteins, primarily cullin subunits of cullin-RING ubiquitin ligases (CRLs). This modification is essential for CRL activity, which controls the ubiquitination and degradation of numerous regulatory proteins involved in cell cycle progression, signal transduction, and transcription. NAE1 is therefore critical for cellular homeostasis and is a validated therapeutic target in cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various) | NAE1 overexpression or mutation leads to dysregulated neddylation, stabilizing CRL substrates (e.g., p27, NRF2) and promoting oncogenic signaling. | COSMIC; PMID: 29301962 |
| Neurodevelopmental disorders | Heterozygous missense variants in NAE1 have been associated with intellectual disability and developmental delay, likely via impaired neddylation of cullins. | ClinVar; PMID: 31036916 |
| Acute myeloid leukemia (AML) | NAE1 is a target of the investigational drug MLN4924 (pevonedistat); sensitivity correlates with NAE1 expression. | COSMIC; PMID: 27058611 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 21.3 | High |
| Bone marrow | 15.8 | Medium |
| Lymph node | 14.2 | Medium |
| Brain (cerebellum) | 12.5 | Medium |
| Liver | 10.1 | Medium |
| Heart | 8.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 (embryonic kidney) | 18.5 | High expression; commonly used for functional studies |
| K562 (leukemia) | 16.2 | Medium; sensitive to NAE inhibition |
| HCT116 (colorectal carcinoma) | 14.8 | Medium; used in MLN4924 studies |
| MCF7 (breast cancer) | 12.3 | Medium |
| A549 (lung cancer) | 11.0 | Medium |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1105G>A (p.Glu369Lys) | Missense | <0.1% (rare) | Reported in neurodevelopmental disorder; likely loss-of-function |
| c.1520A>G (p.Tyr507Cys) | Missense | <0.1% (rare) | ClinVar: uncertain significance; potential dominant-negative effect |
| c.1630C>T (p.Arg544Trp) | Missense | <0.1% (rare) | COSMIC: found in colorectal cancer; functional impact unknown |
Mutation functional classification
Loss of Function (LOF)
Heterozygous missense variants (e.g., p.Glu369Lys) reduce NAE activity, impairing cullin neddylation and CRL function, leading to substrate accumulation and developmental phenotypes.
Gain of Function (GOF)
Not well documented; overexpression of wild-type NAE1 in cancers may enhance neddylation and CRL activity, promoting oncogenesis.
Dominant Negative (DN)
Some missense mutations (e.g., p.Tyr507Cys) may disrupt NAE1-UBA3 interaction, acting as dominant-negative alleles to inhibit neddylation.
View complete mutation data：
Gene Ontology (GO)
| • NEDD8 activating enzyme activity (GO:0019788) | • protein neddylation (GO:0045116) |
| • ubiquitin-like protein conjugating enzyme activity (GO:0061659) | • cullin family protein neddylation (GO:0010388) |
| • cytoplasm (GO:0005737) | • nucleus (GO:0005634) |
Pathways
• Neddylation (R-HSA-8951664)
• Cullin-RING ubiquitin ligase regulation (R-HSA-8951664)
• Ubiquitin-like protein conjugation (R-HSA-8852135)
• Cell cycle (R-HSA-1640170)
Protein Summary
NAE1 (also known as APPBP1) is the 60 kDa regulatory subunit of the NEDD8-activating enzyme (NAE). It forms a heterodimer with the catalytic subunit UBA3. NAE1 binds NEDD8 and facilitates its ATP-dependent activation, transferring NEDD8 to UBA3 for subsequent conjugation to cullins. The protein contains a ubiquitin-fold domain and is essential for CRL-mediated ubiquitination. NAE1 is highly conserved and expressed in most tissues. Its dysregulation is implicated in cancer and developmental disorders.
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