HUWE1: HECT, UBA and WWE Domain Containing E3 Ubiquitin Protein Ligase 1
A critical regulator of protein ubiquitination and degradation, implicated in neurodevelopment and cancer.
Gene Information Card
| Symbol | HUWE1 |
|---|---|
| Full Name | HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | Xp11.22 |
| NCBI Gene ID | 10075 ncbi.nlm.nih.gov/gene/10075 |
| Ensembl ID | ENSG00000086758 |
| UniProt ID | Q7Z6Z7 |
| OMIM ID | 300697 |
| HGNC ID | 24921 |
| Aliases | MULE, ARF-BP1, LASU1, HECTH9, UREB1, KIAA0312, E3Histone, HECTH1 |
Description
HUWE1 encodes a HECT domain-containing E3 ubiquitin ligase that ubiquitinates a wide range of substrates, including p53, MCL1, MYC, and histones. It plays a key role in regulating cell proliferation, apoptosis, DNA damage response, and neurodevelopment. Mutations and dysregulation of HUWE1 are associated with intellectual disability, X-linked syndromic disorders, and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| X-linked intellectual disability, Turner type | Loss-of-function mutations impair ubiquitination of substrates involved in neuronal development | OMIM #300706 |
| Juberg-Marsidi syndrome | Missense mutations in HUWE1 disrupt E3 ligase activity, leading to developmental delay | OMIM #309590 |
| Colorectal cancer | Overexpression of HUWE1 promotes degradation of p53 and MCL1, contributing to tumorigenesis | COSMIC; PMID: 15688013 |
| Breast cancer | HUWE1 amplification leads to increased MYC stability and cell proliferation | COSMIC; PMID: 20534488 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 18.5 | High |
| Testis | 15.2 | High |
| Lung | 10.1 | Medium |
| Liver | 8.3 | Medium |
| Heart | 6.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 22.4 | Embryonic kidney cells; high expression |
| HeLa | 19.8 | Cervical cancer cells; high expression |
| MCF7 | 14.2 | Breast cancer cells; moderate expression |
| HCT116 | 12.6 | Colorectal cancer cells; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.10937G>A (p.Arg3646His) | Missense | Rare | Impaired ubiquitin ligase activity; associated with intellectual disability |
| c.11233C>T (p.Arg3745Trp) | Missense | Rare | Loss of function; linked to Juberg-Marsidi syndrome |
| Amplification | Copy number gain | Frequent in breast cancer | Increased HUWE1 expression; promotes MYC stability |
| Deletion | Copy number loss | Rare | Loss of HUWE1; associated with reduced p53 degradation |
Mutation functional classification
Loss of Function (LOF)
Missense mutations (e.g., p.Arg3646His, p.Arg3745Trp) reduce E3 ligase activity, impairing ubiquitination of substrates like p53 and MCL1, leading to neurodevelopmental disorders.
Gain of Function (GOF)
Gene amplification and overexpression in cancers enhance degradation of tumor suppressors (e.g., p53) and stabilize oncoproteins (e.g., MYC), promoting cell proliferation.
Dominant Negative (DN)
Not well documented; some missense variants may interfere with wild-type HUWE1 function in heterozygous females due to X-inactivation skewing.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Ubiquitin mediated proteolysis (KEGG: hsa04120)
• p53 signaling pathway (KEGG: hsa04115)
• Apoptosis (KEGG: hsa04210)
• Regulation of MYC stability (Reactome: R-HSA-8866654)
Protein Summary
HUWE1 (also known as MULE, ARF-BP1) is a large HECT domain E3 ubiquitin ligase (~482 kDa) that catalyzes the ubiquitination of diverse substrates, including p53, MCL1, MYC, and histones. It contains an N-terminal ubiquitin-associated (UBA) domain, a WWE domain, and a C-terminal HECT domain responsible for ubiquitin transfer. HUWE1 regulates cellular processes such as DNA damage response, apoptosis, cell cycle, and neurodevelopment. Its dysregulation is implicated in X-linked intellectual disability and multiple cancer types.
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