USP15

USP15 (ubiquitin-specific peptidase 15) is a member of the ubiquitin-specific protease family that catalyzes deubiquitination through removal of ubiquitin chains and ubiquitin-substrate conjugates, thereby regulating ubiquitin-dependent cellular processes^[1]. USP15 functions as a critical regulator of TGF-β signaling, where it counteracts ubiquitination-mediated degradation of type I TGF-β receptor (TβRI) and promotes receptor stability and downstream transcriptional responses^[2][3][4]. Mechanistically, USP15 deubiquitinates both TβRI and receptor-regulated SMAD proteins, restoring SMAD transcriptional activity and supporting expression of TGF-β target genes^[2][3][5]. Consequently, USP15 has been implicated in biological processes associated with tissue homeostasis, development, immunity, and cancer-related signaling pathways that depend on TGF-β activity^[2][3]. In disease contexts, elevated USP15 expression or activity has been reported in multiple malignancies, including glioblastoma, breast cancer, and ovarian cancer, where enhanced TGF-β signaling may contribute to tumor progression^[3]. Compared with related DU-family deubiquitinases, USP15 shares structural homology with USP4 and USP11 but exhibits distinct substrate regulation and signaling functions^[1][5]. Notably, both USP15 and USP4 regulate TGF-β pathway components, yet USP15 acts through stabilization of TβRI and deubiquitination of receptor-regulated SMADs, whereas USP4 directly deubiquitinates TβRI to maintain receptor abundance at the plasma membrane^[3][6]. For experimental applications, structurally characterized ubiquitin-variant inhibitors of USP15 have been developed, providing useful tools for investigating USP15-dependent signaling mechanisms and validating therapeutic hypotheses in disease models^[7].