USP9X

Official Full Name

ubiquitin specific peptidase 9 X-linked

Organism

Homo sapiens

GeneID

8239

Background

This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Synonyms

FAF; FAM; hFAM; DFFRX; FAF-X; MRX99; XLID99; MRXS99F;

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Detailed Information

Protein ubiquitination is a reversible reaction, which is constantly opposed by deubiquitination, such as the existence of a large family of deubiquitinating enzymes (DUBs). The human genome encodes about 95 putative DUBs. Among these DUBs, the largest family is the ubiquitin-specific proteases (USPs). The loss of function of each USP is associated with functional consequences, which are often severe. Ubiquitin-specific peptidase 9 X-linked (USP9X) is one of the most studied USPs. It has been reported that USP9X acts in a substrate-specific manner and precisely regulates a variety of cellular processes. In particular, USP9X has been reported to target dozens of proteins to regulate cellular processes, which are fundamental to many aspects of development and disease, namely cell growth and migration, protein trafficking/endocytosis, apoptosis and death, autophagy, polarity, immune response, and stem cell renewal and differentiation. Besides, USP9X has been implicated in a variety of pathological states including Turner syndrome, Parkinson’s disease, X-linked intellectual disability, seizures, and various types of malignancies.

Figure 1. Coordination of USP9X on developmental signalling pathways. (Murtaza M, et al., 2015)

USP9X and Neurological Disorders

USP9X has been implicated in many human neurodevelopmental disorders. Three USP9X mutations have been associated with X-linked intellectual disability. Functional interrogation of these mutations indicated that they were loss of function, because the reductions in axonal growth and neuronal migration observed in mouse neurons lacking Usp9x could be rescued by human wild-type USP9X, but not the mutated forms. That all three mutations are located in the protein's C-terminal region indicates it harbours functions important to neural development, and in particular neural migration and axonal growth. Several lines of evidence show that USP9X also plays an important role in the aetiology of neurodegenerative diseases. The existence of neuronal cytoplasmic inclusions composed of an accumulation of ubiquitylated proteins is a distinctive characteristic of neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's disease. In the brain tissues of PD patients, USP9X colocalises with α-synuclein inclusions, and in vitro studies reveal a functional interaction; although the monoubiquitylated α-synuclein is degraded by the proteasome, USP9X deubiquitylation of α-synuclein directs its degradation by the less efficient autophagy pathway. In patients with PD characterized by proteasomal inhibition, reduced levels of USP9X is also found, which may explain the accumulation of toxic, monoubiquitylated α-synuclein. A role for USP9X in the degradation of accumulated proteins has also been suggested in Alzheimer's and Huntington's disease.

USP9X and Cancer

Usp9x has been described as a key mediator of cell survival. Increased expression of Usp9x is associated with hematologic malignancies including multiple myeloma, chronic myelogenous leukemia, follicular lymphoma, diffuse large B cell lymphoma, as well as solid tumors such as esophageal squamous cell carcinomas, brain tumors, prostate and breast cancers. Overexpression of Usp9x is associated with poor prognosis in multiple myeloma and esophageal squamous cell carcinomas. Interestingly, USP9X can act either as an oncogene or a tumor suppressor, depending on the type of cancer. For example, USP9X inhibited tumor formation by regulating FBW7 protein stability in colorectal cancer. In contrast, Li et al. reported that USP9X was physically associated with centriolar satellite protein CEP131, thus stabilizing CEP131 through its deubiquitinase activity and consequently promoting breast carcinogenesis. In some cancers, USP9X has been shown to modulate chemo-resistance. WP1130 is a partially selective deubiquitinating enzyme inhibitor, which is considered as a potential chemosensitizer due to its ability to inhibit USP9X deubiquitination. This inhibitor represents an emerging class of therapeutics directed against DUBs for the treatment of cancer. Besides, in aggressive B-cell lymphoma, knockdown of USP9X can significantly delay lymphoma development and increase sensitivity to spindle poisons.

References:

Ma T, et al. USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy. Cancer letters, 2018, 436: 129-138.
Chen M, et al. USP9X promotes the progression of hepatocellular carcinoma by regulating beta-catenin. Irish Journal of Medical Science (1971-), 2020: 1-7.
Liu L, et al. Deubiquitinase USP9X promotes cell migration, invasion and inhibits apoptosis of human pancreatic cancer. Oncology Reports, 2017, 38(6): 3531-3537.
Murtaza M, et al. La FAM fatale: USP9X in development and disease. Cellular and molecular life sciences, 2015, 72(11): 2075-2089.
Wang Q, et al. The X-linked deubiquitinase USP9X is an integral component of centrosome. Journal of Biological Chemistry, 2017, 292(31): 12874-12884.
Li X, et al. USP9X regulates centrosome duplication and promotes breast carcinogenesis. Nature communications, 2017, 8(1): 1-16.
Pal A, et al. Usp9x promotes survival in human pancreatic cancer and its inhibition suppresses pancreatic ductal adenocarcinoma in vivo tumor growth. Neoplasia, 2018, 20(2): 152-164.
Zhang C, et al. USP9X destabilizes pVHL and promotes cell proliferation. Oncotarget, 2016, 7(37): 60519.

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