The deubiquitinating enzyme USP8 (ubiquitin-specific peptidase 8; previously named UBPy, ubiquitin-specific processing protease-y) was originally identified as a putative protein encoded by a cDNA expressed in human myeloblasts (hUBPy) and then found, through independent yeast two-hybrid screenings of mouse libraries, as a protein (mUBPy) that interacts with STAM2 (also known as Hbp) and the Ras-guanine nucleotide exchange factor CDC25/RasGRF1. Highly conserved homologues of USP8 have been recently identified in other mammals such as rat (GenBank accession number NP 001099972), macacus (XP 001114466), and ox (NP 001069594), as well as in monotremes (XP 001507996), birds (XP 413830), and amphibians (NP 001080551).canadianneighborpharmacy.com
Moreover, USP8 shares significant homology with deubiquitinating enzymes found in echinoderms, insects, and fungi, in particular with Doa4 of Saccharomyces cerevisiae. Thus, USP8 represents an evolutionarily conserved gene family, and the function of the USP8 gene product itself might be evolution-arily conserved. In vitro studies exploiting the overexpression of recombinant wild-type mouse USP8 and/or dominant negative USP8 mutants reveal that USP8 plays multiple roles at the endosomal compartment, from the crucial function in the down-regulation of tyrosine kinase membrane receptors to the protection of proteins of the endosomal transport machinery from proteasomal degradation and the control of the number and size of endocytic vesicles. USP8 deletion in mice results in embryonic lethality while conditional mouse mutants for the induced deletion of USP8 die 4-6 days after administration of the inducer. Consequently, notwithstanding the fact that there are more than 90 predicted active deubiquitinating enzymes in the mammalian genome, USP8 function in vivo cannot be replaced by other deubiqui-tinases.
Since alternative USP8 animal models, more suitable for understanding its role in vivo, are not presently available, some insight into its function may be gained from the cells that physiologically express the deubiquitinase in high amounts, that is, spermatogenic and neuronal cells. Both of these cell types are characterized by a highly functional polarization of the cell body, and their cell functionality is thought to be strictly dependent on vesicular trafficking and related, ubiquitin-dependent, sorting of protein cargoes.