USP9X (Kr. Xp11.4)
(2554 aminoacid)
- Recommended name: Ubiquitin carboxyl-terminal hydrolase 9X
- Aliases:
- GeneCards Symbol: USP9X 2
- Ubiquitin Specific Peptidase 9 X-Linked 2 3 5
- DFFRX 2 3 4 5
- FAF-X 2 3 5
- MRX99 2 3 5
- FAF 2 3 5
- Ubiquitin Specific Protease 9, X Chromosome (Fat Facets-Like Drosophila) 2 3
- Ubiquitin-Specific Protease 9, X Chromosome 3 4
- Ubiquitin Carboxyl-Terminal Hydrolase 9X 3 4
- Deubiquitinating Enzyme FAF-X 3
- Ubiquitin Thioesterase FAF-X 3 4
- Fat Facets-Like, X-Linked 2 3
- Fat Facets In Mammals 3 4
- HFAM 3 4
- FAM 3 4
- etc
https://www.genecards.org/cgi-bin/carddisp.pl?gene=USP9X&keywords=ubiquitin-specific,protease,X,9
This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases (USPs). 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]
Molecular function for USP9X Gene according to UniProtKB/Swiss-Prot
- Function:
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Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins (PubMed:18254724, 19135894, 22371489, 25944111, 29626158, 30914461, 37454738).
May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin (PubMed:18254724, 19135894, 22371489, 25944111, 29626158, 30914461, 37454738).
Specifically hydrolyzes 'Lys-11'-, followed by 'Lys-63'-, 'Lys-48'- and 'Lys-6'-linked polyubiquitins chains (PubMed:30914461).
Essential component of TGF-beta/BMP signaling cascade (PubMed:19135894).
Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33 (PubMed:19135894).
Deubiquitinates alkylation repair enzyme ALKBH3 (PubMed:25944111).
OTUD4 recruits USP7 and 1 to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors.- Deubiquitinates RNA demethylase enzyme ALKBH5, promoting its stability (PubMed:37454738).2023 Aug;299(8):105055.doi: 10.1016/j.jbc.2023.105055. Epub 2023 Jul 15.Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survivalDeubiquitinates mTORC2 complex component RICTOR at 'Lys-294' by removing 'Lys-63'-linked polyubiquitin chains, stabilizing RICTOR and enhancing its binding to MTOR, thus promoting mTORC2 complex assembly (PubMed:33378666).The mechanistic target of rapamycin complex 2 (mTORC2) controls cell metabolism and survival in response to environmental inputs. Dysregulation of mTORC2 signaling has been linked to diverse human diseases, including cancer and metabolic disorders, highlighting the importance of a tightly controlled mTORC2...Here, we present data, from human cell lines and mice, describing a mechanism by which growth factors regulate ubiquitin-specific protease 9X (USP9X) deubiquitinase to stimulate mTORC2 assembly and activity. USP9X removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 signaling. As mTORC2 is central for cellular homeostasis, understanding the mechanisms regulating mTORC2 activation toward its downstream targets is vital for our understanding of physiological processes and for developing new therapeutic strategies in pathology.
Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres (PubMed:16322459)...Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bi-oriented chromosomes on the metaphase spindle. The chromosome passenger complex containing Survivin and the kinase Aurora B regulates this process from the centromeres. We report that a de-ubiquitinating enzyme, hFAM, regulates chromosome alignment and segregation by controlling both the dynamic association of Survivin with centromeres and the proper targeting of Survivin and Aurora B to centromeres. Survivin is ubiquitinated in mitosis through both Lys(48) and Lys(63) ubiquitin linkages. Lys(63) de-ubiquitination mediated by hFAM is required for the dissociation of Survivin from centromeres, whereas Lys(63) ubiquitination mediated by the ubiquitin binding protein Ufd1 is required for the association of Survivin with centromeres. Thus, ubiquitinaton regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation.
Involved in axonal growth and neuronal cell migration (PubMed:24607389). Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration.
Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein BMAL1 via its deubiquitinating activity (PubMed:29626158).Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1). Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity. Bioluminescence measurement reveals that USP9X knockdown decreases the amplitude of the cellular circadian rhythm but the period and phase are not affected. Our experiments find a new regulator for circadian clock at the post-translational level and demonstrate a different regulatory function for the circadian clock through the deubiquitination and the up-regulation of the core clock protein BMAL1 in the positive limb of the transcription-translation feedback loop.
Acts as a regulator of peroxisome import by mediating deubiquitination of PEX5: specifically deubiquitinates PEX5 monoubiquitinated at 'Cys-11' following its retrotranslocation into the cytosol, resetting PEX5 for a subsequent import cycle (PubMed:22371489).Peroxin 5 (PEX5), the peroxisomal protein shuttling receptor, binds newly synthesized peroxisomal matrix proteins in the cytosol and promotes their translocation across the organelle membrane. During the translocation step, PEX5 itself becomes inserted into the peroxisomal docking/translocation machinery. PEX5 is then monoubiquitinated at a conserved cysteine residue and extracted back into the cytosol in an ATP-dependent manner. We have previously shown that the ubiquitin-PEX5 thioester conjugate (Ub-PEX5) released into the cytosol can be efficiently disrupted by physiological concentrations of glutathione, raising the possibility that a fraction of Ub-PEX5 is nonenzymatically deubiquitinated in vivo.,,,ubiquitin-specific protease 9X (USP9X) is by far the most active deubiquitinase acting on Ub-PEX5, ...USP9X is an elongated monomeric protein with the capacity to hydrolyze thioester, isopeptide, and peptide bonds.
Deubiquitinates PEG10 (By similarity).
Inhibits the activation of the Hippo signaling pathway via deubiquitination of AMOTL2 at 'Lys-347' and 'Lys-408' which prohibits its interaction with and activation of LATS2.
Loss of LATS2 activation and subsequent loss of YAP1 phosphorylation results in an increase in YAP1-driven transcription of target genes (PubMed:26598551, 34404733). LATS1/2 (large tumor suppressor) kinases and the Angiomotin family proteins are potent inhibitors of the YAP (yes-associated protein) oncoprotein, but the underlying molecular mechanism is not fully understood. Here, we report for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition. USP9X_HUMAN,Q93008
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Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins (PubMed:18254724, 19135894, 22371489, 25944111, 29626158, 30914461, 37454738).
- CatalyticActivity:
