VPS25: A Core Component of the ESCRT-II Complex
Essential for Endosomal Sorting, Cytokinetic Abscission, and Autophagy; Implicated in Cancer and Viral Infection
Gene Information Card
| Symbol | VPS25 |
|---|---|
| Full Name | Vacuolar Protein Sorting 25 Homolog |
| Gene Type | Protein coding |
| Chromosomal Location | 17q21.2 |
| NCBI Gene ID | 84313 ncbi.nlm.nih.gov/gene/84313 |
| Ensembl ID | ENSG00000131374 |
| UniProt ID | Q9BRG1 |
| OMIM ID | 610907 |
| HGNC ID | 28122 |
| Aliases | DERP9, EAP20, FAP20, hVPS25 |
Description
VPS25 encodes a 21 kDa protein that is a core component of the endosomal sorting complex required for transport II (ESCRT-II). ESCRT-II is essential for the formation of multivesicular bodies (MVBs), sorting of ubiquitinated membrane proteins into intraluminal vesicles, and subsequent lysosomal degradation. The VPS25 protein directly binds ubiquitin and interacts with other ESCRT subunits (VPS22, VPS36) to form the Y-shaped ESCRT-II complex. Beyond endosomal sorting, VPS25 participates in cytokinetic abscission, autophagy, and exosome biogenesis. It is also hijacked by enveloped viruses (e.g., HIV-1, Ebola) for budding. Dysregulation of VPS25 has been linked to cancer progression and neurodegenerative disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | Altered ESCRT-II function may disrupt growth factor receptor downregulation, leading to sustained proliferative signaling. VPS25 overexpression is reported in breast and lung cancers. | COSMIC; PubMed studies |
| Viral infection (HIV-1, Ebola) | VPS25 is recruited by viral Gag proteins to facilitate membrane scission and viral budding from the host cell. | PubMed; UniProt annotation |
| Neurodegenerative disorders | Impaired ESCRT function can cause accumulation of toxic protein aggregates (e.g., tau, α-synuclein). VPS25 variants are under investigation. | OMIM; research articles |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Lymph node | 12.8 | Medium |
| Bone marrow | 11.5 | Medium |
| Brain (cortex) | 8.3 | Low |
| Liver | 6.1 | Low |
| Heart | 5.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 18.7 | High expression; commonly used for functional studies |
| HeLa | 14.2 | Moderate; validated by RNA-seq |
| K562 | 12.0 | Moderate; leukemia cell line |
| MCF7 | 9.8 | Low-moderate; breast cancer cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1?) | Missense | <0.01% | Likely loss of start codon; predicted loss of function |
| c.214C>T (p.Arg72Cys) | Missense | 0.02% | Substitution in conserved region; functional impact unknown |
| c.340_341insA (p.Gln114fs) | Frameshift | <0.01% | Truncation; loss of ESCRT-II interaction domain |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein or disrupt the core ESCRT-II interface are classified as loss-of-function. These impair MVB sorting and may lead to accumulation of ubiquitinated cargo.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in VPS25. Overexpression in some cancers may act as a dominant effect but is not due to activating mutations.
Dominant Negative (DN)
Missense mutations in the VPS25-VPS22 binding interface (e.g., p.Arg72Cys) could potentially act as dominant-negative by incorporating into ESCRT-II and blocking normal complex assembly, though experimental evidence is limited.
View complete mutation data：
Gene Ontology (GO)
Pathways
• ESCRT-mediated multivesicular body sorting (Reactome: R-HSA-917729)
• Autophagy (KEGG: hsa04140)
• Cytokinetic abscission (Reactome: R-HSA-2467813)
• HIV-1 budding (Reactome: R-HSA-162585)
Protein Summary
VPS25 (UniProt Q9BRG1) is a 176-amino-acid protein with a molecular weight of 20.8 kDa. It contains a winged-helix domain that mediates DNA binding and a C-terminal region that interacts with VPS22 and VPS36 to form the ESCRT-II core. The protein is predominantly cytoplasmic and localizes to endosomal membranes. Post-translational modifications include phosphorylation at Ser-75, which may regulate complex assembly. VPS25 is highly conserved across eukaryotes, underscoring its fundamental role in membrane trafficking.
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