USP9X
Probable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the USP9X gene.[5][6]
Gene
[edit]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.
Function
[edit]Depletion of USP9X from two-cell mouse embryos halts blastocyst development and results in slower blastomere cleavage rate, impaired cell adhesion and a loss of cell polarity. It has also been implicated that USP9X is likely to influence developmental processes through signaling pathways of Notch, Wnt, EGF, and mTOR. USP9X has been recognized in studies of mouse and human stem cells involving embryonic, neural and hematopoietic stem cells.[7] High expression is retained in undifferentiated progenitor and stem cells and decreases as differentiation continues. USP9X is a protein-coding gene that has been implicated either directly through mutations or indirectly in a number of neurodevelopmental and neurodegenerative disorders.
In a knockout model where hippocampal neurons were isolated from an USP9X-knockout male mouse, showed a 43% reduction in axonal length and arborization compared to wild type.[8]
Clinical significance
[edit]Three mutations have been connected with X-linked intellectual disability through disrupted neuronal growth and cell migration. Neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's disease, have also been linked to USP9X. Specifically, USP9X has been implicated in the regulation of the phosphorylation and expression of the microtule-associated protein tau, which forms pathological aggregates in Alzheimer's and other tauopathies.[9]
USP9X syndrome
[edit]Variants of the USP9X gene have been found to cause a neurodevelopmental USP9X syndrome in both males and females. USP9X is strongly evolutionarily conserved in humans and is intolerant to variation. This is due to the important role of the USP9X enzyme, which reverses protein ubiquitylation, thereby decreasing the enzymatic degradation and increasing the longevity of those proteins.[10] Being on the X chromosome, USP9X syndrome manifests differently in females compared to males. In females, loss of function variations in one copy of the gene results in haploinsufficiency. This is because USP9X escapes the usually-protective process of X-inactivation. As a result, even "carrier" females exhibit the syndrome.
Variants found in females with USP9X syndrome include whole or partial deletions of one copy of the USP9X gene, as well as mis-sense mutations or small in-frame deletion mutations.[10] Symptoms in females include intellectual disability, facial dysmorphia, and language impairment. Less common symptoms include short stature, scoliosis, polydactyly, and changes to dentition.[11] Females have a wider range of symptoms than males, likely due to their wider variety of USP9X gene variants compared to males. Other symptoms sometimes found in females but rarely or never in males include hip dysplasia, heart dysmorphia, hearing problems and abnormal skin pigmentation.[10]
USP9X variants seen in surviving males cause loss of function in brain-specific processes only, since total loss of function of this gene is fatal in the embryonic stage. Males are hemizygous for this gene because they possess only one X chromosome. Symptoms seen in affected males include intellectual disability, problems with language, speech, behaviour and sight, and facial dysmorphia. Specific brain abnormalities include white matter disturbances, a thin corpus callosum, and widened ventricles.[12]
Interactions
[edit]USP9X has been shown to interact with:
References
[edit]- 1 2 3 GRCh38: Ensembl release 89: ENSG00000124486 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031010 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ Jones MH, Furlong RA, Burkin H, Chalmers IJ, Brown GM, Khwaja O, et al. (1996). "The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2". Human Molecular Genetics. 5 (11): 1695–1701. doi:10.1093/hmg/5.11.1695. PMID 8922996.
- ↑ "Entrez Gene: USP9X ubiquitin specific peptidase 9, X-linked".
- ↑ Murtaza M, Jolly LA, Gecz J, Wood SA (June 2015). "La FAM fatale: USP9X in development and disease". Cellular and Molecular Life Sciences. 72 (11): 2075–2089. doi:10.1007/s00018-015-1851-0. PMC 4427618. PMID 25672900.
- ↑ "OMIM Entry - * 300072 - Ubiquitin-Specific Protease 9, X-Linked; USP9X". www.omim.org. Retrieved 2016-04-12.
- ↑ Köglsberger S, Cordero-Maldonado ML, Antony P, Forster JI, Garcia P, Buttini M, et al. (December 2017). "Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies". Molecular Neurobiology. 54 (10): 7979–7993. doi:10.1007/s12035-016-0299-z. PMC 5684262. PMID 27878758.
- 1 2 3 Jolly LA, Parnell E, Gardner AE, Corbett MA, Pérez-Jurado LA, Shaw M, et al. (December 2020). "Missense variant contribution to USP9X-female syndrome". npj Genomic Medicine. 5 (1) 53. doi:10.1038/s41525-020-00162-9. PMC 7725775. PMID 33298948.
- ↑ "USP9X". Simons Searchlight. Retrieved 2023-02-22.
- ↑ Johnson BV, Kumar R, Oishi S, Alexander S, Kasherman M, Vega MS, et al. (January 2020). "Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling". Biological Psychiatry. 87 (2): 100–112. doi:10.1016/j.biopsych.2019.05.028. PMC 6925349. PMID 31443933.
- 1 2 Taya S, Yamamoto T, Kanai-Azuma M, Wood SA, Kaibuchi K (December 1999). "The deubiquitinating enzyme Fam interacts with and stabilizes beta-catenin". Genes to Cells. 4 (12): 757–767. doi:10.1046/j.1365-2443.1999.00297.x. PMID 10620020. S2CID 85747886.
- 1 2 Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M, Alessi DR (April 2008). "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains". The Biochemical Journal. 411 (2): 249–260. doi:10.1042/BJ20080067. hdl:2262/45177. PMID 18254724. S2CID 13038944.
- ↑ Taya S, Yamamoto T, Kano K, Kawano Y, Iwamatsu A, Tsuchiya T, et al. (August 1998). "The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme". The Journal of Cell Biology. 142 (4): 1053–1062. doi:10.1083/jcb.142.4.1053. PMC 2132865. PMID 9722616.
- ↑ Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, et al. (2014). "Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer". Proceedings of the National Academy of Sciences of the United States of America. 111 (11): 4251–4256. Bibcode:2014PNAS..111.4251W. doi:10.1073/pnas.1322198111. PMC 3964108. PMID 24591637.
- ↑ Li X, Song N, Liu L, Liu X, Ding X, Song X, et al. (March 2017). "USP9X regulates centrosome duplication and promotes breast carcinogenesis". Nature Communications. 8 (1) 14866. Bibcode:2017NatCo...814866L. doi:10.1038/ncomms14866. PMC 5380967. PMID 28361952.
Further reading
[edit]- D'Andrea A, Pellman D (1998). "Deubiquitinating enzymes: a new class of biological regulators". Critical Reviews in Biochemistry and Molecular Biology. 33 (5): 337–352. doi:10.1080/10409239891204251. PMID 9827704.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–113. doi:10.1006/abio.1996.0138. PMID 8619474.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, et al. (1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–358. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
- Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, et al. (2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–3496. Bibcode:2000PNAS...97.3491D. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
- Murray RZ, Jolly LA, Wood SA (2004). "The FAM deubiquitylating enzyme localizes to multiple points of protein trafficking in epithelia, where it associates with E-cadherin and beta-catenin". Molecular Biology of the Cell. 15 (4): 1591–1599. doi:10.1091/mbc.E03-08-0630. PMC 379258. PMID 14742711.
- Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
- Fu GK, Wang JT, Yang J, Au-Young J, Stuve LL (2004). "Circular rapid amplification of cDNA ends for high-throughput extension cloning of partial genes". Genomics. 84 (1): 205–210. doi:10.1016/j.ygeno.2004.01.011. PMID 15203218.
- Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. (2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
- Al-Hakim AK, Göransson O, Deak M, Toth R, Campbell DG, Morrice NA, et al. (2005). "14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK". Journal of Cell Science. 118 (Pt 23): 5661–5673. doi:10.1242/jcs.02670. PMID 16306228. S2CID 17404931.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–1292. doi:10.1038/nbt1240. PMID 16964243. S2CID 14294292.
- Mouchantaf R, Azakir BA, McPherson PS, Millard SM, Wood SA, Angers A (2006). "The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X". The Journal of Biological Chemistry. 281 (50): 38738–38747. doi:10.1074/jbc.M605959200. PMID 17038327.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983.