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Gene & Protein in Disease Structure and function of USP7

In general, IFN can be divided into three types: (1) diabetic foot, one of the most common complications of a
type I IFN, including IFN-α (20 subtypes) and IFN-β diabetic patients. However, at present, there is no effective
(1 subtype), which are produced mainly by white blood treatment for diabetic foot. USP7 expression is found to
cells, fibroblasts, and virus-infected tissue cells; (2) type II be upregulated in human umbilical vein endothelial cells
IFN, including IFN-γ, and it has only one subtype, which is (HUVECs), when advanced glycation end products are
produced by activated T cells and NK cells; and (3) type III used to establish the diabetic cell model [151] . Inhibition of
IFN, including IFN-γ1, IFN-γ2, and IFN-γ3. The main USP7 was shown to attenuate HUVECs cell cycle arrest
functions of type I IFN are inhibiting viral replication, and cell senescence. It has been further noted that the
providing resistance to parasitic infection, inhibiting mechanism is regulated by USP7, which promotes cycle
cell proliferation, stimulating immune cells, eliciting arrest and senescence of HUVECs cells by regulating the
antitumor activity, and regulating immunomodulatory level of p53 polyubiquitination. The downregulation of
system. Meanwhile, type II IFN possesses antiviral and p53 can reverse USP7-mediated HUVECs cell cycle arrest
anti-proliferation activities, and its main function is in and cell senescence. Treatment of diabetic rat models with
immune regulation [143,144] . For example, in response to USP7 inhibitors can relieve the symptoms of diabetic foot.
virus invasion, the body produces IFN, and the process In conclusion, inhibition of USP7 induces p53 protein
is mediated by several factors. USP7 has been reported degradation and alleviates the symptoms of diabetic foot.
previously as an important negative modulator of virus- These results showed that USP7 is a potential target for the
induced signaling, where USP7 interacts with the E3 Ub treatment of diabetic foot ulcers.
ligase tripartite motif 27 (TRIM27), and their interaction
is further enhanced after virus invasion. In addition, it 6.3. USP7 in pulmonary hypertension
has been reported that TNF receptor-associated factor Pulmonary hypertension is a hemodynamic and
family member-associated NF-κB binding kinase pathophysiological condition in which the pulmonary
(TBK)-1, which phosphorylates IFN regulatory factor artery pressure increases beyond a certain threshold.
(IRF)-3 and IRF-7, promotes the nuclear translocation Pulmonary hypertension can be a group of independent
and induces the expression of antiviral products [145,146] . diseases, complications, or syndromes. Pulmonary
Interestingly, TBK-1 is degraded through the UPP, hypertension can be caused by the changes in the
which is mediated by TRIM27. More remarkably, USP7 pulmonary artery itself, while others factors which can
decreases TBK-1 expression and inhibits IFN antiviral contribute to the development of this disease include
efficacy by stabilizing TRIM27 protein [126] . In another genetic factors, drugs, toxins, and other diseases, such as
example, the suppressor of cytokine signaling 1 is a congenital heart disease [152,153] .
negative regulator of IFN-induced gene expression, which
inhibits IFN antiviral efficacy by interacting with USP7 Recent work has uncovered the role of USP7 in the
through its deubiquitinase activity [54,147,148] . In addition, development of pulmonary hypertension [154] . Abnormal
the p53 protein has been identified as a positive regulator hyperplasia of pulmonary smooth muscle cells (PASMCs)
in response to virus infection [149] . Kaposoi’s sarcoma- is an important pathological feature of pulmonary
associated herpesvirus (KSHV)-encoded viral interferon hypertension, and platelet-derived growth factor (PDGF)-
regulatory factor 4 (vIRF4), is one of the KSHV protein induced PASMCs proliferation is a critical factor in the
which interacts with USP7 and suppresses its enzyme development of pulmonary hypertension. Studies have
activity, resulting in p53 degradation. Further studies revealed that PDGF increases the protein expression of
have identified that vIRF4 stabilizes HDM2 by inhibiting USP7 and its downstream MDM2 and cyclinD1, resulting
its autoubiquitination process, and destabilizes p53 [97,150] . in the induction of PASMCs proliferation. In addition,
The above findings suggest the crucial role of USP7 in downregulation of USP7 can attenuate PDGF-induced
antiviral response; therefore, USP7 can be treated as a MDM2, cyclinD1 stabilization, and cell proliferation.
potential target for antiviral therapy. However, USP7 also On the other hand, MG132 treatment can also abolish
plays an important role in homeostasis of normal cells; PDGF-induced cyclinD1 elevation and cell proliferation.
therefore, these factors should be considered when using In short, inhibition of USP7 activity might be a potential
USP7 inhibitors. therapeutic strategy for the treatment of pulmonary
hypertension. Notably, USP7 inhibits tumor progression
6.2. USP7 in diabetic foot in p53-deficient lung cancer cells, and USP7 maintains
Diabetes mellitus (DM) is a common disease that happens homeostasis in normal cells. Therefore, other factors
worldwide. Blood vessel disorders are frequently seen in should be considered when USP7 inhibitors are used for
patients with DM, and it is commonly associated with pulmonary hypertension.

Volume 1 Issue 2 (2022) 6 https://doi.org/10.36922/gpd.v1i2.118