Page 93 - GPD-1-2

Gene & Protein in Disease Structure and function of USP7

USP7 through binding and rearranging the switching loop 3.1. Targeting monoubiquitination by USP7
in the CD, leading to about 100-fold increase in USP7 In monoubiquitination, a single Ub molecule attaches to
enzymatic activity . In addition, this process can be substrate proteins. PTEN protein, one of the best-known
[30]
increased with the help of allosteric activator guanosine tumor suppressors which is involved in a plethora of
5’-monophosphate synthase (GMPS) , where GMPS can cancer development, is a typical protein that is subject
[32]
binds to UBL1/2/3, subsequently increases the interaction to monoubiquitination. PTEN can be ubiquitinated
between CDs and UBL4/5, thereby promoting the USP7 in various ways, including monoubiquitination, K27-,
activity . This process suggests that the UBL domains are
[32]
indispensable for USP7 to perform its deubiquitinating K48-, and K63- linked polyubiquitination, to modulate
functions. its subcellular localization, aggregation, stability, and
functionality [40-42] . It is known that nuclear localization of
2.3. The CD PTEN is associated with monoubiquitination of PTEN
at K289, which is indispensable for its nuclear import
The CD, which is essential for the cleaving process of and tumor suppression . In addition, USP7 hydrolyzes
[43]
the polyubiquitin chains, in USP7 is composed of 208– monoubiquitination of PTEN, which leads to PTEN nuclear
560 amino acids. It should be noted that the proteolytic exclusion and loss of phosphatase activity, eventually
activity of USP7 is highly diverse and varies depending promoting prostate cancer tumorigenesis. Another
on the specific substrate proteins . The catalytic triad
[25]
contains three types of amino acids, including cystine example is mothers against decapentaplegic homolog
(Cys), histidine (His), and asparagine (Asn)/aspartic 3 (SMAD3) protein. The biological activity of SMAD3
acid (Asp) residues , of which the Asn/Asp residue is depends on the monoubiquitination modification. USP7
[33]
important for polarization of His residue, which in return interacts with SMAD3 and subsequently deubiquitinates
stabilizes the catalytic activity of DUBs . Moreover, the its monoubiquitination level, thereby repressing cancer
[28]
triad is rearranged in the presence of a covalently bound progression in p53-deficient lung cancer. Furthermore,
Ub aldehyde to generate a catalytically competent state USP7 also deubiquitinates monoubiquitination of other
of the CD . It is important to note that, in the absence proteins including forkhead box protein O4, proliferating
[34]
[44-46]
of the UBL domains, the CD will lose almost all of its cell nuclear antigen, histone H2B, and others .
activity. 3.2. Hydrolyzing K48-linked polyubiquitination by
3. USP7 regulates diverse types of USP7
ubiquitination Compared with monoubiquitination, polyubiquitination
is more common in protein modification, and there
DUBs can hydrolyze the polyubiquitin chain of target are seven types of polyubiquitination on thousands of
proteins, thereby protecting them from degradation proteins. At present, USP7 is believed to have the largest
or modulating their function or cellular localization, number of substrate proteins in terms of deubiquitination
depending on the types of ubiquitination process . As as shown in Table 1. It is known that intratumoral hypoxia
[35]
discussed above, ubiquitination is a process that covalently can induce hypoxia-inducible factor 1-alpha (HIF-1α)
attaches a Ub molecule to the specific lysine (K) residue and subsequently promote tumorigenesis, metastasis, and
on a substrate protein. In a Ub molecule, there is a highly treatment resistance. A previous study has revealed that
conserved region, which is composed of the seven lysine USP7 can remove the K48-linked polyubiquitination by
residues, namely, K6, K11, K27, K29, K23, K48, and K63, physically interacts with HIF-1α, thereby increasing the
which may lead to the diverse forms of Ub modification. protein stability and resulting in tumor cell epithelial-
Based on the Ub chain, Ub modifications could be classified mesenchymal transition, metastasis, and tumor
into monoubiquitination (substrate protein tagged with progression .
[47]
a single Ub molecule) and polyubiquitination (substrate
protein tagged with a multiple Ub molecule), and according In addition, ADP-ribosylation factor 4 (ARF4) is a small
to the Ub binding sites, ubiquitination are accordingly guanine nucleotide-binding protein, which belongs to Ras
named K6-, K11-, K27-, K29-, K23-, K48-, and K63- superfamily of small G proteins. Previous studies have
linked ubiquitination . Importantly, USP7 can hydrolyze demonstrated that ARF4 is an anti-apoptotic protein, which
[36]
almost all types of Ub through monoubiquitination as acts as a BAX inhibitor, and its function is indispensable in
well as K48- and K63-linked polyubiquitination [10,37] . glioblastoma tumorgenesis [52,115] . Interestingly, USP7 has
Furthermore, USP7 has been shown to markedly reduce been shown to be significantly upregulated in glioblastoma
the polyubiquitination levels of the substrate proteins, patient samples. Further study revealed that USP7 directly
thereby exerting diverse functions [20,38,39] . binds to ARF4, catalyzes the removal of the K48-linked

Volume 1 Issue 2 (2022) 3 https://doi.org/10.36922/gpd.v1i2.118