USP7 (Ubiquitin-Specific Peptidase 7, also HAUSP; encoded by the USP7 gene) is a major deubiquitinating enzyme (DUB) that removes ubiquitin from target proteins, rescuing them from proteasomal degradation. USP7 is a critical regulator of the p53/MDM2 axis, epigenetic maintenance, and neuronal proteostasis.
USP7 is a 128 kDa cysteine protease belonging to the ubiquitin-specific protease (USP) family of deubiquitinating enzymes[1]. It removes ubiquitin moieties from over 70 known substrates, with functional consequences ranging from protein stabilization to altered signaling. USP7's role in balancing the ubiquitin-proteasome system makes it relevant to neurodegenerative protein aggregation disorders. [1]
| | | [2]
|---|---| [3]
| Protein Name | USP7 (HAUSP) | [4]
| Gene | USP7 |
| UniProt ID | Q93009 |
| Molecular Weight | 128 kDa |
| Length | 1,102 amino acids |
| Subcellular Localization | Nucleus (nuclear bodies), cytoplasm |
| Enzymatic Activity | Cysteine protease; deubiquitinating enzyme |
USP7 has a modular five-domain architecture[1]:
USP7's catalytic domain adopts an auto-inhibited conformation in isolation[2]:
This auto-inhibition provides a safeguard against uncontrolled deubiquitination.
USP7 recognizes substrates primarily through its TRAF-like domain[3]:
| Substrate | Pathway | Consequence of Deubiquitination |
|---|---|---|
| p53 | Tumor suppression | Stabilization → cell cycle arrest/apoptosis |
| MDM2 | p53 regulation | Stabilization → increased p53 degradation |
| DNMT1 | DNA methylation | Maintains DNA methylation patterns |
| UHRF1 | Epigenetic maintenance | Chromatin remodeling |
| FOXP3 | Treg function | Stabilizes master Treg transcription factor |
| PTEN | PI3K/Akt signaling | Nuclear PTEN stabilization |
| BMI1/RING1B | Polycomb silencing | Maintains H2A ubiquitination |
| β-catenin | Wnt signaling | Promotes Wnt target gene expression |
In the nervous system, USP7 serves essential functions[4]:
USP7 has been identified as a tau deubiquitinase with implications for AD[5]:
USP7 operates in balance with the ubiquitination machinery[3]:
| Interactor | Binding Site | Function |
|---|---|---|
| Ubiquitin | Catalytic domain | Substrate for cleavage |
| p53 | TRAF domain (P/AxxS) | Tumor suppressor stabilization |
| MDM2 | TRAF domain | E3 ligase stabilization |
| GMP synthetase (GMPS) | UBL4-5 | Allosteric activator |
| DNMT1 | TRAF domain | DNA methyltransferase stabilization |
| WASH complex | TRAF domain | Endosomal recycling regulation |
| ICP0 (HSV) | TRAF domain | Viral immune evasion |
Multiple USP7-selective inhibitors have been developed for oncology[6]:
Faesen AC et al. Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase (2011). 2011. ↩︎
Hao YH et al. USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder (2015). 2015. ↩︎
Bhatt DG et al. USP7 as a deubiquitinase for tau: implications for Alzheimer's disease (2020). 2020. ↩︎
Turnbull AP et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors (2017). 2017. ↩︎