Ubiquitin-Specific Protease 7, or USP7, is a protein found within human cells that functions as a deubiquitinase. This enzyme plays a role in regulating the lifespan of other proteins by removing small tags called ubiquitin. Through this action, USP7 helps maintain balance within cells, influencing various cellular processes and contributing to overall cellular health.
Understanding USP7’s Role in the Body
Deubiquitinases (DUBs) like USP7 act as molecular scissors, removing ubiquitin tags from proteins. By cleaving these tags, USP7 prevents target proteins from being marked for degradation by the cell’s waste disposal system, the proteasome. This stabilization allows proteins to perform their functions for longer durations.
USP7 participates in maintaining protein stability across numerous cellular functions. It helps regulate proteins involved in important processes like the DNA damage response, ensuring the integrity of genetic material. For example, USP7 stabilizes proteins such as MDC1, which are important for detecting and repairing double-strand DNA breaks.
Beyond DNA repair, USP7 also influences cell cycle regulation, which governs cell growth and division. It controls the activity of proteins like cyclin F and CDK1, ensuring proper cell progression and preventing uncontrolled proliferation. USP7 is also involved in modulating immune responses. It can deubiquitinate and stabilize components of pathways such as NF-κB, a master regulator of inflammation and immunity.
USP7’s Connection to Major Diseases
Dysregulation of USP7, through overactivity or genetic mutations, can disrupt cellular processes, contributing to various diseases. In many cancers, USP7 becomes overactive, stabilizing proteins that promote tumor growth and survival. For instance, USP7 can deubiquitinate and stabilize MDM2, an E3 ubiquitin ligase that targets the tumor suppressor protein p53 for degradation.
By stabilizing MDM2, USP7 indirectly promotes the degradation of p53, a protein that normally halts cell growth or initiates cell death in response to DNA damage or other stresses. This action allows cancer cells to evade natural safeguards and continue proliferating. High USP7 expression is observed in various cancers, including breast, prostate, colon, and multiple myeloma, and is linked to more aggressive tumors and reduced effectiveness of therapies.
USP7 is also implicated in neurodevelopmental disorders. Pathogenic mutations in the USP7 gene cause Hao-Fountain syndrome, a rare genetic condition. Individuals with this syndrome experience global developmental delays, intellectual disability, and significant speech impairment.
In addition to its roles in cancer and neurodevelopmental disorders, USP7 is exploited by certain viruses, particularly herpesviruses, to aid their life cycles. Viruses such as Herpes Simplex Virus (HSV) and Epstein-Barr Virus (EBV) encode proteins that interact with USP7. These viral proteins can manipulate USP7’s deubiquitinating activity to stabilize viral proteins or evade the host’s immune defenses, facilitating viral replication and persistence within the host.
Targeting USP7 for Medical Advancements
Given its widespread involvement in disease pathways, USP7 has emerged as a promising target for therapeutic development. Researchers are developing small-molecule USP7 inhibitors designed to block its deubiquitinase activity. The goal of these inhibitors is to destabilize USP7’s target proteins, particularly those that contribute to disease progression.
In cancer, inhibiting USP7 can lead to the degradation of oncogenic proteins like MDM2, thereby reactivating tumor suppressors such as p53, which can then induce cell cycle arrest or programmed cell death in cancer cells. This strategy aims to reverse the cancer-promoting effects of overactive USP7. Preclinical studies have shown that USP7 inhibitors can reduce the viability of various cancer cell lines and inhibit tumor growth in animal models.
Despite promising preclinical results, no USP7 inhibitors have yet advanced into human clinical trials. Challenges in drug development include achieving high selectivity to avoid off-target effects and optimizing pharmacokinetic properties for effective delivery and action within the body. However, the unique structural flexibility of USP7’s catalytic domain offers multiple potential binding sites, which researchers are exploring to design more potent and selective compounds. Understanding USP7’s roles continues to open new avenues for drug discovery, not only for cancer but also for immune disorders and viral infections, highlighting its broad therapeutic potential.