USP7 explained

Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.[1] [2] [3] [4]

Function

Regulation of the p53 tumor suppressor

USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates.[5] Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins.

HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53.[6] Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress.

Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.

Role in transcriptional regulation

USP7 can deubiquitinate histone H2B and this activity is associated with gene silencing in Drosophila.[7] USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B.[7] The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silencing of homeotic genes.[8] USP7 also controls histone H2A monoubiquitylation (H2AK119ub1), known to repress gene expression, by noncanonical Polycomb-repressive complexes (ncPRC1s).[9]

Role in drug addiction

USP7, in conjunction with the scaffold protein Maged1, mediates the monoubiquitination of histone H2A in the paraventricular thalamus, a non-canonical reward region of the brain.[10] [11] This modification is significantly increased in response to chronic cocaine use, contributing to cocaine-adaptive behaviors and transcriptional repression in mice. Furthermore, genetic variations in MAGED1 and USP7 are associated with altered susceptibility to cocaine addiction and cocaine-induced behaviors in humans. These findings reveal an important epigenetic mechanism involving USP7 that regulates the risk and behavioral response to cocaine addiction, positioning USP7 as a potential therapeutic target for cocaine use disorder.

Association with herpesviruses

USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virus (HSV), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0.

More recently, an interaction between USP7 and the EBNA1 protein of Epstein–Barr virus (EBV) (another herpesvirus) was also discovered.[12] This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences.[13] USP7 was shown to be important for histone H2B deubiquitination in human cells and for deubiquitination of histone H2B incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression.

The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes.

Binding partners

The following is a list of some of the known cellular binding partners of USP7/HAUSP:

Interactions

USP7 has been shown to interact with Ataxin 1,[16] CLSPN,[17] P53, and more recently with MAGED1 and histone H2A through its function in the polycomb repressive complex. A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7.[18]

Clinical significance

Loss-of-function mutations of USP7 are associated with neurodevelopmental disorder whose symptoms include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal,[19] [20]

USP7 can be used as a senolytic agent due to ubiquitination and subsequent proteasome degradation of mdm2, thereby increasing p53 activity.

Further reading

Notes and References

  1. Puente XS, Sánchez LM, Overall CM, López-Otín C . Human and mouse proteases: a comparative genomic approach . Nature Reviews. Genetics . 4 . 7 . 544–58 . Jul 2003 . 12838346 . 10.1038/nrg1111 . 2856065 .
  2. Robinson PA, Lomonte P, Markham AF, Everett RD . Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization . Cytogenetics and Cell Genetics . 83 . 1–2 . 100 . Mar 1999 . 9925944 . 10.1159/000015142 . 2024-07-12 . 34084848 .
  3. Web site: Entrez Gene: USP7 ubiquitin specific peptidase 7 (herpes virus-associated).
  4. Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J . A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein . The EMBO Journal . 16 . 7 . 1519–30 . Apr 1997 . 9130697 . 1169756 . 10.1093/emboj/16.7.1519 .
  5. Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L . Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP . The Journal of Biological Chemistry . 278 . 48 . 47753–61 . Nov 2003 . 14506283 . 10.1074/jbc.M307200200 . free .
  6. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W . Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization . Nature . 416 . 6881 . 648–53 . Apr 2002 . 11923872 . 10.1038/nature737 . 2002Natur.416..648L . 4389394 .
  7. van der Knaap JA, Kumar BR, Moshkin YM, Langenberg K, Krijgsveld J, Heck AJ, Karch F, Verrijzer CP . GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7 . Molecular Cell . 17 . 5 . 695–707 . Mar 2005 . 15749019 . 10.1016/j.molcel.2005.02.013 . free .
  8. van der Knaap JA, Kozhevnikova E, Langenberg K, Moshkin YM, Verrijzer CP . Biosynthetic enzyme GMP synthetase cooperates with ubiquitin-specific protease 7 in transcriptional regulation of ecdysteroid target genes . Molecular and Cellular Biology . 30 . 3 . 736–44 . Feb 2010 . 19995917 . 2812229 . 10.1128/MCB.01121-09 .
  9. Sijm . Ayestha . Atlasi . Yaser . van der Knaap . Jan A. . Wolf van der Meer . Joyce . Chalkley . Gillian E. . Bezstarosti . Karel . Dekkers . Dick H. W. . Doff . Wouter A. S. . Ozgur . Zeliha . van IJcken . Wilfred F. J. . Demmers . Jeroen A. A. . Verrijzer . C. Peter . USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3 . Science Advances . 8 . 44 . eabq7598 . 2022 . 10.1126/sciadv.abq7598 .
  10. Cheron J, Beccari L, Hagué P, Icick R, Despontin C, Carusone T, Defrance M, Bhogaraju S, Martin-Garcia E, Capellan R, Maldonado R, Vorspan F, Bonnefont J, de Kerchove d'Exaerde A . 6 . USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder . Nature Communications . 14 . 1 . 8481 . December 2023 . 38123574 . 10733359 . 10.1038/s41467-023-44120-2 . 2023NatCo..14.8481C .
  11. Zhou K, Zhu Y . The paraventricular thalamic nucleus: A key hub of neural circuits underlying drug addiction . Pharmacological Research . 142 . 70–76 . April 2019 . 30772461 . 10.1016/j.phrs.2019.02.014 .
  12. Holowaty MN, Frappier L . HAUSP/USP7 as an Epstein-Barr virus target . Biochemical Society Transactions . 32 . Pt 5 . 731–2 . Nov 2004 . 15494000 . 10.1042/BST0320731 .
  13. Sarkari F, Sanchez-Alcaraz T, Wang S, Holowaty MN, Sheng Y, Frappier L . EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein-Barr virus latent origin of DNA replication . PLOS Pathogens . 5 . 10 . e1000624 . Oct 2009 . 19834552 . 2757719 . 10.1371/journal.ppat.1000624 . Speck SH . free .
  14. He Y, Li W, Lv D, Zhang X, Zhang X, Ortiz YT, Budamagunta V, Campisi J, Zheng G, Zhou D . Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity . . 19 . 3 . e13117 . 2020 . 10.1111/acel.13117 . 7059172 . 32064756.
  15. Schwertman P, Lagarou A, Dekkers DH, Raams A, van der Hoek AC, Laffeber C, Hoeijmakers JH, Demmers JA, Fousteri M, Vermeulen W, Marteijn JA . UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair . Nature Genetics . 44 . 5 . 598–602 . May 2012 . 22466611 . 10.1038/ng.2230 . 5486230 .
  16. Hong S, Kim SJ, Ka S, Choi I, Kang S . USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product . Molecular and Cellular Neurosciences . 20 . 2 . 298–306 . June 2002 . 12093161 . 10.1006/mcne.2002.1103 . 41295664 .
  17. Faustrup H, Bekker-Jensen S, Bartek J, Lukas J, Mailand N . USP7 counteracts SCFbetaTrCP- but not APCCdh1-mediated proteolysis of Claspin . The Journal of Cell Biology . 184 . 1 . 13–19 . January 2009 . 19124652 . 2615094 . 10.1083/jcb.200807137 .
  18. Sowa ME, Bennett EJ, Gygi SP, Harper JW . Defining the human deubiquitinating enzyme interaction landscape . Cell . 138 . 2 . 389–403 . July 2009 . 19615732 . 2716422 . 10.1016/j.cell.2009.04.042 .
  19. Hao YH, Fountain MD, Fon Tacer K, Xia F, Bi W, Kang SH, Patel A, Rosenfeld JA, Le Caignec C, Isidor B, Krantz ID, Noon SE, Pfotenhauer JP, Morgan TM, Moran R, Pedersen RC, Saenz MS, Schaaf CP, Potts PR . USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder . Mol. Cell . 59 . 6 . 956–69 . September 2015 . 26365382 . 4575888 . 10.1016/j.molcel.2015.07.033 .
  20. Web site: USP7 Related Diseases . National Organization for Rare Disorders (NORD) .