Probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X)
The protein contains 2570 amino acids for an estimated molecular weight of 292280 Da.
Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-48'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration (PubMed:16322459, PubMed:18254724, PubMed:19135894, PubMed:24607389). Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein ARNTL/BMAL1 via its deubiquitinating activity (PubMed:29626158). (updated: Dec. 5, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
Biological Process
Amyloid fibril formation
Axon extension
BMP signaling pathway
Cell cycle
Cell division
Cell migration
Cellular protein metabolic process
Cerebellar cortex structural organization
Chromosome segregation
Female gamete generation
Gene expression
Hippocampus development
In utero embryonic development
Mitotic nuclear division
Negative regulation of transcription by RNA polymerase II
Neuron migration
Positive regulation of DNA demethylation
Post-embryonic development
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein deubiquitination
Protein deubiquitination involved in ubiquitin-dependent protein catabolic process
Protein localization
Protein stabilization
Protein targeting to peroxisome
Protein ubiquitination
Regulation of circadian rhythm
Regulation of proteasomal protein catabolic process
Rhythmic process
Transcription initiation from RNA polymerase II promoter
Transcription, DNA-templated
Transforming growth factor beta receptor signaling pathway
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 300072
Ubiquitin-specific protease 9, x-linked; usp9x
Drosophila fat facets-related, x-linked; dffrx
Fam
DESCRIPTION
The USP9X gene encodes a large substrate-specific deubiquitylating enzyme (summary by Homan et al., 2014).CLONING
Jones et al. (1996) reported that an expressed sequence tag (EST 221) derived from human adult testis shares homology with the Drosophila fat facets (faf) gene. They detected related sequences on both the human X and Y chromosomes. They used EST 221 to derive clones covering the complete open reading frame of the X-specific locus, which they termed DFFRX. Y-specific cDNA clones were derived, and they termed that locus DFFRY (400005). Over the 2 regions corresponding to nucleotides 6 to 1901 and nucleotides 5815 to 7907 of the DFFRX sequence, the X- and Y-specific sequences share 91% and 88% identity, respectively. Both putative gene products contain conserved cysteine and histidine domains that have been described in ubiquitin C-terminal hydrolases (e.g., 191342). Northern blot analysis of 16 different adult human tissues with the EST 221 revealed expression in all tissues. They also detected both DFFRX and DFFRY expression in developing human tissues.GENE FUNCTION
Jones et al. (1996) determined the X inactivation status of DFFRX through use of quantitative RT-PCR with X-specific primers and found that the level of DFFRX expression rises as the copy number of the X chromosome increases, indicating that DFFRX escapes inactivation. In Drosophila the faf gene has been shown to be important in eye function and in oocyte development. The high degree of conservation between the Drosophila faf gene and the DFFRX sequence led Jones et al. (1996) to conclude that DFFRX has an important function in humans. Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bioriented chromosomes on the metaphase spindle. The chromosome passenger complex containing survivin (603352) and the kinase aurora B (604970) regulates this process from the centromeres. Vong et al. (2005) reported that a deubiquitinating enzyme, FAM, also known as USP9X, 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 lys48 and lys63 ubiquitin linkages. Lys63 deubiquitination mediated by FAM is required for the dissociation of survivin from centromeres, whereas lys63 ubiquitination mediated by the ubiquitin-binding protein UFD1 (601754) is required for the association of survivin with centromeres. Thus, ubiquitination regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation. Schwickart et al. (2010) showed that the deubiquitinase USP9X binds to and stabilizes MCL1 (159552) and removes the lys48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlated with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increased MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. Schwickart et al. (2010) concluded that their results identified USP9X as a prognostic and therapeutic target and showed that deubiquitinases may stabilize labile oncoproteins in human malignancies.MAPPING ... More on the omim web site
Dec. 9, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
April 27, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300072 was added.