*2.5. Cushing Disease*

Mutations of the ubiquitin-specific peptidase 8 (USP8) are associated with pituitary adenoma tumors, also called Cushing disease [68] (Table 1). In Cushing disease, the adrenocorticotropic hormone (ACTH)-producing pituitary adenoma tumors secrete cortisol in the blood, resulting in obesity, diabetes, hypertension as well as additional cerebrovascular, cardiac, and reproductive disorders [107]. Disease-associated *USP8* mutations are located within or adjacent to the 14-3-3 binding motif. The diminished ability of mutant UPS8 to interact with 14-3-3 proteins enhances the proteolytic cleavage of USP8, leading to the generation of an activated catalytic fragment [69].

Enhanced activity of mutant USP8 in Cushing disease impairs the down-regulation of the epidermal growth factor receptor (EGFR) pathway due to increased EGFR deubiquitination. Consequently, sustained EGFR signaling in pituitary adenoma leads to enhanced promoter activity of the gene encoding proopiomelanocortin (POMC), the precursor of ACTH [63,64]. However, a subset of *USP8* mutations are not associated with higher EGFR expression, and mutations in *USP8* rarely occur in other tumor types, suggesting that USP8-dependent mechanisms other than EGFR up-regulation cannot be ruled out to be responsible for the pathogenesis of Cushing disease [66].

The role of USP8 in endosomal sorting complexes required for transport (ESCRT)-mediated trafficking of RTKs remains controversial [108]. USP8 contains an N-terminal microtubule interacting and transport domain, which has unveiled its potential to interact with charged multivesicular body proteins (CHMP), components of the ESCRT-III complex [67]. One of the proposed mechanisms is the regulation of multi-monoubiquitination of charged multivesicular body protein 1b (CHMP1B) [65]. CHMP1B, a part of the endosomal ESCRT-III complex involved in endosomal budding, is multi-monoubiquitinated in response to growth factor stimulation [65]. Deubiquitination of CHMP1B favors its assembly into a membrane-associated ESCRT-III polymer complexes and modulates the dynamics of endosomal sorting [65]. Further studies on the USP8 targets may shed new light on our understanding of USP8 contribution to membrane receptor tra fficking and chemotherapy resistance in Cushing's disease.
