Ubiquitin specific peptidase 8 (USP8)

Ubiquitin specific peptidase 8 (USP8) is a multidomain deubiquitinating enzyme of the ubiquitin-specific protease family that catalyzes the removal of ubiquitin molecules from substrate proteins, thereby reversing their ubiquitination[3][7]. USP8 plays an essential role in endosomal sorting, trafficking, and degradation or recycling of membrane receptors, including receptor tyrosine kinases such as EGFR, as well as key proteins involved in autophagy and the endosomal system[1][5][7]. Its activity controls the intracellular fate of signaling receptors and impacts numerous processes including cell proliferation, cell cycle progression, apoptosis, selective autophagy, and immune system function[2][4][6]. Germline USP8 loss is embryonic lethal in animal models, and tissue-specific ablation is associated with severe immune or liver phenotypes[2][3]. Somatic gain-of-function mutations in USP8 are a key driver in corticotroph pituitary microadenomas causing Cushing’s disease, and overexpression or mutation of USP8 contributes to cancer progression and chemoresistance in several tumor types[2][6]. USP8's biological regulation involves autoinhibition, 14-3-3 protein binding, and complex domain structure[4]. This enzyme represents a promising candidate for pharmacological intervention in cancer, neurodegenerative diseases, and endocrine tumors, but safety concerns remain substantial due to its critical cellular roles[6].

Other names

Ubiquitin carboxyl-terminal hydrolase 8UBPYKIAA0055hUBPyHumORF8SPG59Deubiquitinating enzyme 8Ubiquitin isopeptidase YUbiquitin thioesterase 8Ubiquitin-specific-processing protease 8PITA4

Inhibition of USP8 increases ubiquitination of target proteins, alters degradation of receptor tyrosine kinases and membrane proteins, impairs recycling and signaling of growth factor receptors, and can induce apoptosis or sensitize cells to other therapies[1][6].