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Gene & Protein in Disease Structure and function of USP7

suppression. The tumor suppressive role of p53 protein Table 2. Signaling pathway regulated by USP7
has been widely reported, and as a transcriptional factor,
p53 regulates numerous physiology processes, such as Signaling pathway Ref Signaling pathway Ref
cell cycle, DNA damage repair, cell apoptosis, antitumor p300-p53/p21 pathway [128] BCR-ABL signaling [38]
activity, and cell stress response [116] . In contrast, mutations EZH2-CCF-cGAS [129] MDM2/MDMX-p53 [130]
and dysregulation of p53 have been reported to occur in signaling pathway
more than 50% of all malignancies, leading to the loss of FBP1-DNMT1 pathway [131] NEDD4L-SMAD pathway [132]
its antitumor activity [117] . The stability of p53 is regulated Cell cycle and EMT [133] JMJD3/CLU signaling [81]
through the UPP and its polyubiquitination, and mediated pathway
by HDM2, an E3 Ub ligase [118] . Interestingly, HDM2 is p53/TfR1 pathway [134] Wnt/β-catenin signaling [39]
also degraded through the UPP in an autoubiquitination PI3K/Akt pathway [124] Hippo pathway [107]
pattern, at the same time p53 and HDM2 interacts with Akt/ERK signaling [135] NF-κB signaling [136]
each other by forming a feedback loop [119] . Interestingly, AMPK pathway [124] Shh pathway [16]
USP7 can regulate both p53 and mouse double minute
2 homolog (MDM2). USP7 interacts with p53 through NOX4/NLRP3 pathway [137] Glucose Metabolism [138]
signaling
its TRAF-like domain and stabilizes the p53 protein
level by decreasing its ubiquitination level, even in the So×9-PTHrP-PTH1R [58] Insulin/IGF-1-like [88]
signaling
axis
[24]
presence of HDM2 . Meanwhile, USP7 also binds with
[21]
HDM2 and inhibits its polyubiquitination . Thus, these HIF-1α signaling [139] Hedgehog signaling [140]
pathway
three proteins form a complex, as evidenced by their Shoc2-ERK1/2 pathway [141] p53-MDM2 pathway [21]
crystal structure analyses, where both HDM2 and p53
interacts with the TRAF-like domain of USP7, further, the
interaction of HDM2/USP7 is closer than p53/USP7 [120,121] . systems, USP7 directly interacts with and stabilizes
The previous studies have shown that partial knockdown of Axin protein by decreasing its polyubiquitination and
USP7 induces the degradation of p53, while the complete inhibiting the Wnt/β-catenin pathway thereby suppressing
[39]
inhibition of USP7 expression leads to the stabilization Wnt-induced osteoblast differentiation . In addition,
of p53, and this phenomenon is related to HDM2 [21,122] . Hippo pathway is essential to the organ development,
Another study reported that USP7 stabilizes both p53 and and its deregulation has been identified in a wide variety
HDM2 protein in vivo. However, it is believed that USP7 of tumors. Further, a transcription coactivator Yorkie
maintains HDM2 to a certain protein level, to regulate the has been demonstrated to be stabilized by USP7 in
polyubiquitination degradation of p53. hepatocellular carcinoma (HCC) cells; interestingly, this
protein is the upstream of the Hippo signaling [107] . Taken
In addition, UPS7 has been shown to have other together, USP7, which regulates Hippo pathway, could
substrate proteins, including PTEN, c-Maf, MafB, trans- bea potential therapeutic target for HCC. In addition,
activator of transcription, NAD-dependent deacetylase the nuclear factor kappa light chain enhancer of activated
sirtuin-1, BCR-ABL, GATA-binding factor 1 (also known B cells (NF-κB) signal transduction pathway has been
as GATA1), and ring finger protein 168 [10,20,21,24,38,49,51,110,123] . described previously to participate in the development and
Many of these proteins are associated with cell cycle, DNA dysfunction of the immune system. Most of the proteins
damage, regulation of transcription, and tumorigenesis. In in this pathway are known to regulate biological processes,
addition, some of the substrate proteins have been shown such as innate and adaptive immunity, inflammation,
to function as a mediator in certain signaling pathways, and stress responses. USP7 stabilizes NF-κB signaling
indicating the complexity of the substrate proteins function and increases its transcription, leading to the expression
in human cells, thus, more studies are required to explore of downstream genes in response to the immune system
and understand its functions. activation [127] .

5. USP7 modulates signaling transduction 6. USP7 and diseases
It has been reported that USP7 is involved in multiple
cellular signaling pathways, such as PI3K/PTEN/AKT 6.1. The roles of USP7 in viral infection and
signaling [10,124] , Wnt/β-catenin signaling , Hippo inflammation
[39]
pathway [107] , NF-κB signaling [125] , type I IFN signaling [126] , Interferon (IFN) is a low molecular glycoprotein induced
and DNA damage signaling [110] (Table 2). These pathways by virus, bacteria, and IFN inducers acting on cells. IFN
have different effects on cells, although their activities is not toxic to the cell itself, but it inhibits the replication
are regulated by USP7. For example, in multiple cellular of a variety of viruses and possesses antitumor activity [142] .

Volume 1 Issue 2 (2022) 5 https://doi.org/10.36922/gpd.v1i2.118