USP8
Ubiquitin Specific Peptidase 8
Gene Information Card
| Symbol | USP8 |
|---|---|
| Full Name | Ubiquitin Specific Peptidase 8 |
| Gene Type | Protein coding |
| Chromosomal Location | 15q21.2 |
| NCBI Gene ID | 9101 ncbi.nlm.nih.gov/gene/9101 |
| Ensembl ID | ENSG00000138592 |
| UniProt ID | P40818 |
| OMIM ID | 603158 |
| HGNC ID | 12606 |
| Aliases | UBPY, hUBPY, FLJ41048, MGC15619 |
Description
USP8 encodes a deubiquitinating enzyme that removes ubiquitin from target proteins, regulating endosomal sorting, receptor trafficking, and growth factor signaling. It is critical for maintaining EGFR stability and is frequently mutated in corticotroph pituitary adenomas, leading to Cushing's disease.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cushing's disease | Gain-of-function mutations in USP8 increase deubiquitinase activity, preventing EGFR downregulation and promoting ACTH secretion in pituitary corticotroph adenomas. | PMID: 25693187, 25693188 |
| Pituitary adenoma (corticotroph) | Somatic USP8 mutations (e.g., p.Ser718Pro) enhance catalytic activity, leading to increased POMC transcription and ACTH production. | PMID: 25693187 |
| Breast cancer | USP8 overexpression correlates with poor prognosis; promotes EGFR recycling and sustained signaling. | PMID: 23319689 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.3 | Medium |
| Pituitary | 15.1 | Medium |
| Testis | 8.7 | Low |
| Kidney | 6.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 18.5 | High expression |
| HeLa | 14.2 | Medium expression |
| MCF7 | 11.0 | Medium expression |
| HepG2 | 9.8 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Ser718Pro | Missense | ~36% in sporadic Cushing's disease | Gain-of-function; increases deubiquitinase activity |
| p.Pro720Arg | Missense | ~10% in sporadic Cushing's disease | Gain-of-function; enhances EGFR recycling |
| p.Asp724Gly | Missense | Rare | Gain-of-function; similar mechanism |
Mutation functional classification
Loss of Function (LOF)
Not commonly reported; experimental knockdown reduces cell proliferation.
Gain of Function (GOF)
Common in Cushing's disease; mutations in the 14-3-3 binding motif increase catalytic activity and EGFR stability.
Dominant Negative (DN)
Not described for USP8.
View complete mutation data：
Gene Ontology (GO)
| • thiol-dependent deubiquitinase (GO:0004843) | • ubiquitin-dependent protein catabolic process (GO:0006511) |
| • endocytosis (GO:0006897) | • protein ubiquitination (GO:0016567) |
| • cytoplasmic vesicle (GO:0031410) | • cytoplasm (GO:0005737) |
Pathways
• Endosomal trafficking (R-HSA-199991)
• EGFR downregulation (R-HSA-177929)
• Ubiquitin-mediated proteolysis (KEGG hsa04120)
Protein Summary
USP8 is a 1118-amino acid deubiquitinating enzyme containing a catalytic USP domain and a SH3-binding motif. It removes ubiquitin from endocytosed receptors such as EGFR, preventing lysosomal degradation and promoting recycling. In Cushing's disease, somatic gain-of-function mutations in the 14-3-3 binding site increase its activity, leading to sustained EGFR signaling and ACTH hypersecretion.
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