Ubiquitin-specific protease 8 (USP8)

Ubiquitin-specific protease 8 (USP8), also known as UBPY, is a critical deubiquitinating enzyme belonging to the cysteine protease family that regulates protein stability and endosomal trafficking [1, 6]. It plays a central role in the endosomal sorting of various transmembrane receptors, most notably the epidermal growth factor receptor (EGFR), by removing ubiquitin chains to prevent their lysosomal degradation [1, 11]. In clinical pathology, gain-of-function mutations in the 14-3-3 binding motif of USP8 are a primary driver of Cushing's disease, leading to constitutive enzyme activation, EGFR stabilization, and excessive adrenocorticotropic hormone (ACTH) secretion from pituitary adenomas [2, 6, 14]. Furthermore, USP8 is frequently overexpressed in multiple cancers, including breast, lung, and glioblastoma, where it stabilizes oncogenic proteins and promotes tumor progression, metastasis, and immune evasion [3, 8, 10, 17]. Pharmacological inhibition of USP8 is currently being explored as a therapeutic strategy to induce the degradation of these stabilized substrates, thereby suppressing tumor growth and hormonal hypersecretion [5, 14, 15]. However, because USP8 is essential for fundamental processes such as liver function and immune homeostasis, therapeutic development faces significant challenges regarding potential systemic toxicity [7, 12].

Other names

UBPYUbiquitin carboxyl-terminal hydrolase 8Deubiquitinating enzyme 8Ubiquitin isopeptidase YUbiquitin thiolesterase 8HumORF8

Inhibition of deubiquitinating activity, leading to the accumulation of polyubiquitinated substrate proteins (e.g., EGFR, TβRII, POMC, PD-L1) and their subsequent degradation via the proteasomal or lysosomal pathways [5, 6, 14, 15].