Ubiquitin specific peptidase 9 X-linked (USP9X)

Ubiquitin specific peptidase 9 X-linked (USP9X) is a highly conserved deubiquitinating enzyme located on the X chromosome and a member of the ubiquitin-specific protease (USP) family. Its catalytic domain features a canonical USP fold with palm, thumb, and fingers subdomains, a zinc finger motif, and a β-hairpin insertion important for substrate recognition and linkage specificity. USP9X cleaves ubiquitin from substrate proteins, preferentially targeting lysine 11-, 48-, 63-, and 6-linked polyubiquitin chains, thus stabilizing diverse proteins. Biologically, USP9X is critical in protein stability, cell polarity, centrosome function, apoptosis, cell migration, stem cell renewal, and major signaling pathways such as Hippo signaling, in which it stabilizes key members including LATS kinase and WW45. The function of USP9X is highly context-dependent: it has been linked to both tumor suppression (e.g., via Hippo pathway activation in pancreatic and breast cancer) and oncogenesis (with overexpression in some cancers correlating with poor prognosis). Germline mutations in USP9X are associated with X-linked intellectual disability and neurodevelopmental syndromes. USP9X inhibitors, such as WP1130, are under investigation as potential therapeutics, but development faces challenges due to the enzyme’s involvement in critical cellular processes and potential tissue-specific adverse effects.

Other names

Ubiquitin carboxyl-terminal hydrolase 9XDFFRXFAMUSP9hFAMFAFFAF-XMRX99Deubiquitinating enzyme FAF-XFat facets in mammalsFat facets protein-relatedX-linkedUbiquitin thioesterase FAF-XUbiquitin-specific protease 9X chromosomeUbiquitin-specific-processing protease FAF-Xfat facets-likeMRXS99FXLID99Drosophila fat facets relatedprobable ubiquitin carboxyl-terminal hydrolase FAF-X

Inhibitors block the deubiquitinating activity of USP9X, leading to enhanced ubiquitin-mediated degradation of USP9X substrates and modulation of cell signaling pathways