Ubiquitin-specific-processing protease 7 (USP7)

Ubiquitin-specific-processing protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme that plays a pivotal role in maintaining protein homeostasis by removing ubiquitin chains from target substrates to prevent their proteasomal degradation. It is most notably recognized for its complex regulation of the p53-MDM2 axis, where it stabilizes the E3 ligase MDM2, thereby promoting the degradation of the p53 tumor suppressor. Beyond p53, USP7 modulates a wide array of proteins involved in DNA repair, epigenetic silencing, and immune evasion, often acting as an oncogene when overexpressed in various malignancies such as multiple myeloma and prostate cancer. In the context of viral infection, USP7 is exploited by herpesviruses to stabilize viral proteins like ICP0, facilitating viral replication and latency. Therapeutic strategies focus on small-molecule inhibitors that disrupt USP7 activity to restore p53 function, induce apoptosis in cancer cells, and impair the immunosuppressive activity of regulatory T cells. While several potent and selective inhibitors have shown significant preclinical efficacy, none have yet advanced to clinical approval.

Other names

HAUSPHerpesvirus-associated ubiquitin-specific proteaseUbiquitin carboxyl-terminal hydrolase 7Ubiquitin-specific peptidase 7TEF1HAFOUS

Inhibition of deubiquitinating activity through covalent modification of the catalytic cysteine or non-covalent allosteric binding, leading to the destabilization and degradation of oncogenic substrates (e.g., MDM2, N-Myc) and the stabilization of tumor suppressors (e.g., p53, PTEN).