| Gene |
[USP15](/genes/usp15) |
| UniProt |
Q9Y4E8 |
| PDB |
5CHA, 5OJB |
| Mol. Weight |
106 kDa (872 amino acids) |
| Localization |
Cytoplasm, nucleus |
| Family |
USP (Ubiquitin-specific peptidase) family |
| Chromosome |
12q14.1 |
| Diseases |
[ALS](/diseases/als), [PD](/diseases/pd), [Cancer](/diseases/cancer) |
USP15 is a deubiquitinating enzyme (DUB) that plays critical roles in the ubiquitin-proteasome system, regulating protein stability, signaling pathways, and cellular stress responses. USP15 dysfunction has been implicated in neurodegenerative diseases including ALS and PD.
USP15 (Ubiquitin-specific peptidase 15) is a 106 kDa protein encoded by the USP15 gene on chromosome 12q14.1 . It belongs to the USP family of cysteine proteases that remove ubiquitin from substrate proteins .
USP15 contains several functional domains:
- N-terminal DUSP (Domain in USP) domain: Regulatory functions
- USP catalytic domain: Cysteine protease activity for ubiquitin removal
- S1 and S2 ubiquitin-binding sites: Substrate recognition
- Q QDE motif: Characteristic of the USP subfamily
The enzyme exists in multiple conformations, with active and inactive states regulated by substrate binding .
In the healthy nervous system, USP15 performs essential functions:
- Protein Quality Control: Removes ubiquitin chains, preventing proteasomal degradation
- NF-κB Signaling: Regulates inflammatory responses
- DNA Repair: Modulates DNA damage response pathways
- Wnt Signaling: Controls β-catenin stability
- Synaptic Plasticity: Regulates AMPA receptor trafficking
- Stress Response: Handles misfolded protein accumulation
USP15 is implicated in ALS through multiple mechanisms:
- TDP-43 Metabolism: Regulates TDP-43 ubiquitination and clearance
- Proteostasis: Controls protein aggregate clearance
- Oxidative Stress: Modulates antioxidant responses
- Mitochondrial Function: Affects mitochondrial protein quality control
In PD, USP15 involvement includes:
- α-Synuclein Clearance: Regulates ubiquitination and degradation
- Parkin Function: Modulates parkin-mediated mitophagy
- Dopaminergic Neuron Survival: Affects neuronal viability
- LRRK2 Pathway: Interacts with LRRK2 signaling
- Alzheimer's Disease: Modulates APP and tau degradation
- Huntington's Disease: Affects mutant huntingtin clearance
- Multiple System Atrophy: Implicated in oligodendrocyte dysfunction
- USP15 Inhibitors: Small molecules targeting catalytic activity
- Allosteric Modulators: Compounds affecting protein-protein interactions
- Proteostasis Modulators: Enhancing compensatory clearance pathways
- USP15 Overexpression: Enhancing protein quality control
- Modulating Substrate Specificity: Altering USP15 function
- With Proteasome Inhibitors: Enhancing proteotoxic stress in disease
- With Autophagy Inducers: Synergistic clearance of aggregates