The USP7 protein interaction network and its roles in tumorigenesis

Abstract

Ubiquitin-specific protease (USP7), also known as Herpesvirus-associated ubiquitin-specific protease (HAUSP), is a deubiquitinase. There has been significant recent attention on USP7 following the discovery that USP7 is a key regulator of the p53-MDM2 pathway. The USP7 protein is 130 kDa in size and has multiple domains which bind to a diverse set of proteins. These interactions mediate key developmental and homeostatic processes including the cell cycle, immune response, and modulation of transcription factor and epigenetic regulator activity and localization. USP7 also promotes carcinogenesis through aberrant activation of the Wnt signalling pathway and stabilization of HIF-1α. These findings have shown that USP7 may induce tumour progression and be a therapeutic target. Together with interest in developing USP7 as a target, several studies have defined new protein interactions and the regulatory networks within which USP7 functions. In this review, we focus on the protein interactions of USP7 that are most important for its cancer-associated roles.

Keywords: Cancer; Deubiquitinase; Protein network; Protein–protein interaction; Proteomics; USP7.

Figure 1

Key elements of the ubiquitin-proteasome system (UPS). Ubiquitin conjugation itself is mediated by the E1-E2-E3 enzymes respectively with the ubiquitin ligases (E3) targeting the ubiquitin to specific substrates. Deubiquitinase proteins (DUBs), (indicated by ∗) are proteases that act to cleave ubiquitin from substrate proteins and one of the most important effects of this is to antagonize the targeting of proteins for proteasomal degradation.

Figure 2

Overview of motif structure of the USP7 protein showing the TNF-receptor associated factor (TRAF) domain, papain-like catalytic domain (Catalytic), and multiple Ubiquitin-like (Ubl) domains. The TRAF and Ubl domains of USP7 mediate distinct protein–protein interactions.

Figure 3

A summary of the roles and known interaction partners of USP7 in cancer. The principal known processes and pathways within which USP7 functions are shown in orange and known interaction partners and substrates corresponding to these functional categories are shown in green.