Ubiquitin-specific-processing protease 22 (USP22) (USP22)

Ubiquitin-specific-processing protease 22 (USP22) is a member of the ubiquitin-specific protease family and a key enzymatic subunit of the SAGA transcriptional coactivator complex [2, 4]. It functions as a deubiquitinase that removes monoubiquitin from histones H2A and H2B, thereby regulating chromatin structure and gene expression [2, 10]. Beyond histones, USP22 stabilizes several critical oncogenic proteins, such as c-Myc, SIRT1, and Cyclin D1, which drive cell cycle progression and inhibit apoptosis [3, 5]. The protein is frequently overexpressed in various human cancers, including lung, breast, and colorectal carcinomas, where it correlates with poor clinical outcomes and metastasis [11, 18]. USP22 also plays a significant role in immune evasion by downregulating MHC-I molecules, helping tumor cells avoid detection by the immune system [14, 16]. Due to its central role in promoting tumor growth and therapy resistance, USP22 is considered a high-value therapeutic target [2, 7]. While no drugs are currently approved, experimental inhibitors such as macrocyclic peptides and repurposed compounds like Ergotamine are being investigated for their ability to block its catalytic activity [6, 7]. Targeting USP22 has shown potential in sensitizing resistant tumors to both conventional chemotherapy and modern immune checkpoint inhibitors [13, 14]. However, therapeutic development must account for its essential role in normal physiology, as loss of USP22 is associated with embryonic lethality and placental defects [15].

Other names

Ubiquitin carboxyl-terminal hydrolase 22Ubiquitin specific peptidase 22Deubiquitinating enzyme 22Ubiquitin thioesterase 22KIAA1063USP3L

USP22 inhibitors act by binding to the catalytic domain or disrupting the assembly of the SAGA deubiquitinating module, thereby preventing the removal of ubiquitin from substrates like histones H2B, c-Myc, and SIRT1, which leads to their degradation or functional inactivation [2, 6].