USP9X
Description
The USP9X (ubiquitin specific peptidase 9 X-linked) is a protein-coding gene located on chromosome X.
USP9X (Ubiquitin carboxyl-terminal hydrolase 9X) is an enzyme encoded by the USP9X gene in humans. It belongs to the peptidase C19 family and is similar to ubiquitin-specific proteases. USP9X escapes X-inactivation, despite being located on the X chromosome. Its depletion in mouse embryos halts blastocyst development, leading to slower blastomere cleavage rate, impaired cell adhesion, and loss of cell polarity. USP9X is linked to developmental processes through signaling pathways of Notch, Wnt, EGF, and mTOR. It is highly expressed in undifferentiated progenitor and stem cells and decreases as differentiation proceeds. USP9X has been implicated in neurodevelopmental and neurodegenerative disorders. Mutations in USP9X are associated with X-linked intellectual disability due to disrupted neuronal growth and cell migration. It is also linked to Alzheimer's, Parkinson's, and Huntington's disease. USP9X regulates the phosphorylation and expression of tau, a protein involved in pathological aggregates in these diseases. Studies on USP9X-knockout mice showed a significant reduction in axonal length and arborization in hippocampal neurons compared to wild type.
USP9X is a deubiquitinase that plays a role in both the processing of ubiquitin precursors and ubiquitinated proteins. It prevents protein degradation by removing conjugated ubiquitin, thereby regulating protein turnover. Specifically, it hydrolyzes Lys-63-, Lys-48-, Lys-29-, and Lys-33-linked polyubiquitin chains. USP9X is a key component of the TGF-beta/BMP signaling cascade, specifically deubiquitinating monoubiquitinated SMAD4 and opposing the activity of TRIM33, an E3 ubiquitin-protein ligase. It also deubiquitinates ALKBH3, an alkylation repair enzyme, and promotes its stability in cooperation with OTUD4 and USP7. USP9X further deubiquitinates RICTOR, a component of the mTORC2 complex, by removing Lys-63-linked polyubiquitin chains, stabilizing RICTOR and enhancing its binding to MTOR, ultimately promoting mTORC2 complex assembly. USP9X also regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Additionally, it is involved in axonal growth and neuronal cell migration. USP9X regulates cellular clock function by enhancing the protein stability and transcriptional activity of BMAL1, a core circadian protein, through its deubiquitinating activity. It also acts as a regulator of peroxisome import by mediating the deubiquitination of PEX5, specifically deubiquitinating PEX5 monoubiquitinated at Cys-11 following its retrotranslocation into the cytosol, resetting PEX5 for subsequent import cycles. USP9X interacts with SMAD4, MARK4, NUAK1, BIRC5/survivin, DCX, OTUD4, and USP7.
USP9X is also known as DFFRX, FAF, FAF-X, FAM, MRX99, MRXS99F, XLID99, hFAM.
Associated Diseases
- Mental retardation, X-linked 99
- X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
- Mental retardation, X-linked 99, syndromic, female-restricted
