Ubiquitin-specific peptidase 10 and 13 (USP10/USP13)

Ubiquitin-specific peptidase 10 (USP10) and Ubiquitin-specific peptidase 13 (USP13) are deubiquitinating enzymes (DUBs) that play pivotal roles in maintaining protein stability and cellular homeostasis by removing ubiquitin chains from substrate proteins (1.1.2, 1.1.3). They are frequently characterized as a dual therapeutic target because they form a functional complex with Beclin-1, a key regulator of autophagy, where they mutually stabilize each other and the Beclin-1/Vps34 complex (1.3.4, 1.4.3). Beyond their joint role in autophagy, USP10 is a critical regulator of the tumor suppressor p53 and the stress granule protein G3BP1, while USP13 modulates the stability of proteins such as PTEN, MITF, and c-Myc (1.1.1, 1.4.1). In many human cancers, including melanoma, lung, and ovarian cancer, these enzymes are often overexpressed, contributing to tumor progression and chemoresistance by stabilizing oncogenic factors or inhibiting autophagy-mediated cell death (1.2.3, 1.3.1). The small molecule Spautin-1 is the most prominent drug candidate that dually inhibits USP10 and USP13, leading to the degradation of Beclin-1 and potent inhibition of autophagy, which has shown promise in sensitizing cancer cells to treatments like imatinib and cisplatin (1.3.2, 1.3.3).

Other names

Ubiquitin-specific peptidase 10Ubiquitin-specific peptidase 13USP10USP13Ubiquitin carboxyl-terminal hydrolase 10Ubiquitin carboxyl-terminal hydrolase 13Isopeptidase T-like protein 1ISOT3Deubiquitinating enzymes

Dual inhibition of the deubiquitinating activity of USP10 and USP13, leading to the accelerated degradation of Beclin-1 and the subsequent inhibition of the Vps34 phosphatidylinositol 3-kinase complex, which blocks the initiation of autophagy.