Disease relevance of USP7

• Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7 [1].
• Based on a thorough analysis of the properties of an HSV-1 mutant virus that expresses forms of ICP0 that are unable to bind to USP7, we conclude that USP7-mediated stabilization of ICP0 is dominant over ICP0-induced degradation of USP7 during productive HSV-1 infection [1].
• HAUSP/USP7 as an Epstein-Barr virus target [2].
• In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression [3].
• In addition, the simultaneous evaluation of both HAUSP expression and p53 gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840, p = 0.0357) [3].

High impact information on USP7

• Here, we report the crystal structures of the 40 kDa catalytic core domain of HAUSP in isolation and in complex with ubiquitin aldehyde [4].
• The HeLa cell protein TEF-1 binds specifically and cooperatively to two SV40 enhancer motifs of unrelated sequence [5].
• In contrast, TEF-1 and a second SV40 enhancer binding protein, TEF-2, bind independently to templates containing the cognate motifs of both proteins (GT-I and either GT-IIC or Sph motifs) even though these motifs cooperate in enhancer activity in vivo [5].
• These findings reveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also imply that HAUSP might function as a tumour suppressor in vivo through the stabilization of p53 [6].
• Similar to USP7, mutations in GMPS acted as enhancers of Pc in vivo [7].

Biological context of USP7

• Using partial proteolysis of USP7 coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we showed that USP7 comprises four structural domains; an N-terminal domain known to bind p53, a catalytic domain, and two C-terminal domains [8].
• These mechanisms occur independently of ICP0 and its ability to sequester USP7 and may differ from those initiated in response to DNA damage [9].
• The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7 [10].
• Impact of the interaction between herpes simplex virus type 1 regulatory protein ICP0 and ubiquitin-specific protease USP7 on activation of adeno-associated virus type 2 rep gene expression [11].
• Concerning tumour histology, HAUSP mRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas (p = 0.0038), while the frequency of p53 mutation was significantly higher in squamous cell carcinomas than in adenocarcinomas (p = 0.0461) [3].

Anatomical context of USP7

• In serum-deprived differentiated smooth muscle cells, TEF-1 was redistributed to the nucleus, and this correlated with increased activity of the alpha-Tm promoter [12].
• This site can bind transcription enhancer factor-1 (TEF-1) present in muscle cells both in vitro and in vivo [12].
• Interestingly, human (h)TEF-5 is specifically expressed in the differentiated syncytiotrophoblast of the human term placenta and its expression is upregulated during the differentiation of cytotrophoblasts to syncytiotrophoblast in vitro, whereas that of hTEF-1 is down-regulated [13].

Associations of USP7 with chemical compounds

• Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial [10].
• We purified USP7 from embryo nuclear extracts as a stable heteromeric complex with guanosine 5'-monophosphate synthetase (GMPS) [7].
• While the majority of these changes were silent, TEF-2 and TEF-3 differed from TEF-1 by having a lysine instead of a glutamate at amino acid position 41 [14].

Physical interactions of USP7

• Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization [15].
• Using mutant Vmw110 viruses we show that the RING finger domain of Vmw110 is essential for the induced degradation of DNA-PKcs but that the ability of Vmw110 to bind to a cellular ubiquitin-specific protease (HAUSP) is not required [16].

Regulatory relationships of USP7

• However, USP7 does negatively regulate FOXO transcriptional activity towards endogenous promoters [17].
• FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP [17].

Other interactions of USP7

• The TD of MUL also interacted with itself, whereas the TDs of USP7 and SPOP did not self-associate [18].
• Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide [10].
• These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway [10].
• Oxidative stress-induced ubiquitination and deubiquitination by USP7 do not influence FOXO protein half-life [17].
• Quantitative reverse-transcription polymerase chain reaction (RT-PCR) was performed to evaluate the gene expression of HAUSP, p21, and bax [3].

Analytical, diagnostic and therapeutic context of USP7

• Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization [19].
• HAUSP Northern blot analysis demonstrated several-fold differences in gene expression that did not correlate with p53 alterations [20].

References