Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7

Chavoshi, Sara; Egorova, Olga; Lacdao, Ira Kay; Farhadi, Sahar; Sheng, Yi; Saridakis, Vivian

doi:10.1074/jbc.M115.710632

Title: Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7

Journal Article · Tue Jan 19 00:00:00 UTC 2016 · Journal of Biological Chemistry

DOI: https://doi.org/10.1074/jbc.M115.710632 · OSTI ID:1252771

Chavoshi, Sara ^[1]; Egorova, Olga ^[1]; Lacdao, Ira Kay ^[1]; Farhadi, Sahar ^[1]; Sheng, Yi ^[1]; Saridakis, Vivian ^[1]

York Univ., Toronto, ON (Canada)

Viral interferon regulatory factor 1 (vIRF1), a Kaposi sarcoma herpesvirus protein, destabilizes p53 by inhibiting p53 acetylation and Hdm2 phosphorylation. This leads to increased ubiquitination and degradation of p53 by Hdm2, which cripples the cellular p53-mediated antiviral response. Ubiquitin-specific protease 7 (USP7) deubiquitinates p53 and Hdm2 and regulates their stability. We identified an EGPS consensus sequence in vIRF1, which is identical to that found in Epstein-Barr virus nuclear antigen 1 (EBNA1) that interacts with the N-terminal domain of USP7 (USP7-NTD). GST pulldown assays demonstrated that vIRF1 interacts with USP7-NTD via its EGPS motif. NMR heteronuclear single quantum correlation (HSQC) analysis revealed chemical perturbations after titration of USP7-NTD with vIRF1 ⁴⁴SPGEGPSGTG⁵³ peptide. In contrast, these perturbations were reduced with a mutant vIRF1 peptide, ⁴⁴SPGEGPAGTG⁵³. Fluorescence polarization analysis indicated that the vIRF1 peptide interacted with USP7-NTD with a K_d of 2.0 μm. The crystal structure of the USP7-NTD·vIRF1 peptide complex revealed an identical mode of binding as that of the EBNA1 peptide to USP7-NTD. We also showed that USP7 interacts with vIRF1 in U2OS cells. Decreased levels of p53, but not Hdm2 or ataxia telangiectasia-mutated (ATM), were seen after expression of vIRF1, but not with a vIRF1 mutant protein. Furthermore, our results support a new role for vIRF1 through deregulation of the deubiquitinating enzyme USP7 to inhibit p53-mediated antiviral responses.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Canada Foundation for Innovation Leaders Opportunity Fund Program; Canadian Inst. of Health Research (CIHR); Ontario Research Fund Research Infrastructure Program

OSTI ID:: 1252771

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 12 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (48)

Herpes Simplex Virus Type 1 Immediate-Early Protein Vmw110 Binds Strongly and Specifically to a 135-kDa Cellular Protein Meredith, Michayla; Orr, Anne; Everett, Roger Virology, Vol. 200, Issue 2 https://doi.org/10.1006/viro.1994.1209	journal	May 1994
Crystal Structure of a UBP-Family Deubiquitinating Enzyme in Isolation and in Complex with Ubiquitin Aldehyde Hu, Min; Li, Pingwei; Li, Muyang Cell, Vol. 111, Issue 7 https://doi.org/10.1016/S0092-8674(02)01199-6	journal	December 2002
Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV Moore, Patrick S.; Chang, Yuan Trends in Genetics, Vol. 14, Issue 4 https://doi.org/10.1016/S0168-9525(98)01408-5	journal	April 1998
The Viral Etiology of AIDS‐Associated Malignancies Angeletti, Peter C.; Zhang, Luwen; Wood, Charles HIV-1: Molecular Biology and Pathogenesis https://doi.org/10.1016/S1054-3589(07)56016-3	book	January 2008
Further Insight into Substrate Recognition by USP7: Structural and Biochemical Analysis of the HdmX and Hdm2 Interactions with USP7 Sarkari, Feroz; La Delfa, Anthony; Arrowsmith, Cheryl H. Journal of Molecular Biology, Vol. 402, Issue 5 https://doi.org/10.1016/j.jmb.2010.08.017	journal	October 2010
Structure of the p53 Binding Domain of HAUSP/USP7 Bound to Epstein-Barr Nuclear Antigen 1 Saridakis, Vivian; Sheng, Yi; Sarkari, Feroz Molecular Cell, Vol. 18, Issue 1 https://doi.org/10.1016/j.molcel.2005.02.029	journal	April 2005
Loss of HAUSP-Mediated Deubiquitination Contributes to DNA Damage-Induced Destabilization of Hdmx and Hdm2 Meulmeester, Erik; Maurice, Madelon M.; Boutell, Chris Molecular Cell, Vol. 18, Issue 5 https://doi.org/10.1016/j.molcel.2005.04.024	journal	May 2005
Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase Faesen, Alex C.; Dirac, Annette M. G.; Shanmugham, Anitha Molecular Cell, Vol. 44, Issue 1 https://doi.org/10.1016/j.molcel.2011.06.034	journal	October 2011
“Add to Subtract”: A Simple Method to Remove Complex Background Signals from the ¹ H Nuclear Magnetic Resonance Spectra of Mixtures Ye, Tao; Zheng, Cheng; Zhang, Shucha Analytical Chemistry, Vol. 84, Issue 2 https://doi.org/10.1021/ac202548n	journal	December 2011
Structural basis for self-association and receptor recognition of human TRAF2 Park, Young Chul; Burkitt, Vicki; Villa, Anthony R. Nature, Vol. 398, Issue 6727 https://doi.org/10.1038/19110	journal	April 1999
Disruption of HAUSP gene stabilizes p53 Cummins, Jordan M.; Rago, Carlo; Kohli, Manu Nature, Vol. 428, Issue 6982 https://doi.org/10.1038/nature02501	journal	April 2004
Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization Li, Muyang; Chen, Delin; Shiloh, Ariel Nature, Vol. 416, Issue 6881 https://doi.org/10.1038/nature737	journal	March 2002
Version 1.2 of the Crystallography and NMR system Brunger, Axel T. Nature Protocols, Vol. 2, Issue 11 https://doi.org/10.1038/nprot.2007.406	journal	October 2007
Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies Bernardi, Rosa; Pandolfi, Pier Paolo Nature Reviews Molecular Cell Biology, Vol. 8, Issue 12 https://doi.org/10.1038/nrm2277	journal	December 2007
Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein Lee, Hye-Ra; Choi, Won-Chan; Lee, Stacy Nature Structural & Molecular Biology, Vol. 18, Issue 12 https://doi.org/10.1038/nsmb.2142	journal	November 2011
Molecular recognition of p53 and MDM2 by USP7/HAUSP Sheng, Yi; Saridakis, Vivian; Sarkari, Feroz Nature Structural & Molecular Biology, Vol. 13, Issue 3 https://doi.org/10.1038/nsmb1067	journal	February 2006
Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage Chehab, N. H.; Malikzay, A.; Stavridi, E. S. Proceedings of the National Academy of Sciences, Vol. 96, Issue 24 https://doi.org/10.1073/pnas.96.24.13777	journal	November 1999
Phosphorylation of p53 Serine 15 Increases Interaction with CBP Lambert, Paul F.; Kashanchi, Fatah; Radonovich, Michael F. Journal of Biological Chemistry, Vol. 273, Issue 49 https://doi.org/10.1074/jbc.273.49.33048	journal	December 1998
Ubiquitin-specific Protease 7 Is a Regulator of Ubiquitin-conjugating Enzyme UbE2E1 Sarkari, Feroz; Wheaton, Keith; La Delfa, Anthony Journal of Biological Chemistry, Vol. 288, Issue 23 https://doi.org/10.1074/jbc.M113.469262	journal	April 2013
The Herpes Simplex Virus Type 1 (HSV-1) Regulatory Protein ICP0 Interacts with and Ubiquitinates p53 Boutell, Chris; Everett, Roger D. Journal of Biological Chemistry, Vol. 278, Issue 38 https://doi.org/10.1074/jbc.M300776200	journal	July 2003
Protein Interaction Domains of the Ubiquitin-specific Protease, USP7/HAUSP Holowaty, Melissa N.; Sheng, Yi; Nguyen, Tin Journal of Biological Chemistry, Vol. 278, Issue 48 https://doi.org/10.1074/jbc.M307200200	journal	September 2003
Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation Feng, Jianhua; Tamaskovic, Rastislav; Yang, Zhongzhou Journal of Biological Chemistry, Vol. 279, Issue 34 https://doi.org/10.1074/jbc.M404936200	journal	May 2004
ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins de Castro, E.; Sigrist, C. J. A.; Gattiker, A. Nucleic Acids Research, Vol. 34, Issue Web Server https://doi.org/10.1093/nar/gkl124	journal	July 2006
The crystal structure of the DNA-binding domain of vIRF-1 from the oncogenic KSHV reveals a conserved fold for DNA binding and reinforces its role as a transcription factor Hew, Kelly; Dahlroth, Sue-Li; Venkatachalam, Rajakannan Nucleic Acids Research, Vol. 41, Issue 7 https://doi.org/10.1093/nar/gkt082	journal	February 2013
The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0 Maul, G. G.; Everett, R. D. Journal of General Virology, Vol. 75, Issue 6 https://doi.org/10.1099/0022-1317-75-6-1223	journal	June 1994
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Data processing and analysis with the autoPROC toolbox Vonrhein, Clemens; Flensburg, Claus; Keller, Peter Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911007773	journal	March 2011
Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma Chang, Y.; Cesarman, E.; Pessin, M. Science, Vol. 266, Issue 5192 https://doi.org/10.1126/science.7997879	journal	December 1994
Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas Chen, W.; Hilton, I. B.; Staudt, M. R. Journal of Virology, Vol. 84, Issue 8 https://doi.org/10.1128/JVI.01321-09	journal	February 2010
A Survey of the Interactome of Kaposi's Sarcoma-Associated Herpesvirus ORF45 Revealed Its Binding to Viral ORF33 and Cellular USP7, Resulting in Stabilization of ORF33 That Is Required for Production of Progeny Viruses Gillen, Joseph; Li, Wenwei; Liang, Qiming Journal of Virology, Vol. 89, Issue 9 https://doi.org/10.1128/JVI.02925-14	journal	February 2015
Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response Salsman, J.; Jagannathan, M.; Paladino, P. Journal of Virology, Vol. 86, Issue 2 https://doi.org/10.1128/JVI.05442-11	journal	November 2011
The Ubiquitin-Specific Protease USP7 Modulates the Replication of Kaposi's Sarcoma-Associated Herpesvirus Latent Episomal DNA Jager, W.; Santag, S.; Weidner-Glunde, M. Journal of Virology, Vol. 86, Issue 12 https://doi.org/10.1128/JVI.06840-11	journal	April 2012
Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Binds to p53 and Represses p53-Dependent Transcription and Apoptosis Seo, T.; Park, J.; Lee, D. Journal of Virology, Vol. 75, Issue 13 https://doi.org/10.1128/JVI.75.13.6193-6198.2001	journal	July 2001
Inhibition of p53 Tumor Suppressor by Viral Interferon Regulatory Factor Nakamura, H.; Li, M.; Zarycki, J. Journal of Virology, Vol. 75, Issue 16 https://doi.org/10.1128/JVI.75.16.7572-7582.2001	journal	August 2001
Short Duration of Elevated vIRF-1 Expression during Lytic Replication of Human Herpesvirus 8 Limits Its Ability To Block Antiviral Responses Induced by Alpha Interferon in BCBL-1 Cells Pozharskaya, V. P.; Weakland, L. L.; Zimring, J. C. Journal of Virology, Vol. 78, Issue 12 https://doi.org/10.1128/JVI.78.12.6621-6635.2004	journal	May 2004
Reciprocal Activities between Herpes Simplex Virus Type 1 Regulatory Protein ICP0, a Ubiquitin E3 Ligase, and Ubiquitin-Specific Protease USP7 Boutell, C.; Canning, M.; Orr, A. Journal of Virology, Vol. 79, Issue 19 https://doi.org/10.1128/JVI.79.19.12342-12354.2005	journal	September 2005
Inhibition of the ATM/p53 Signal Transduction Pathway by Kaposi's Sarcoma-Associated Herpesvirus Interferon Regulatory Factor 1 Shin, Y. C.; Nakamura, H.; Liang, X. Journal of Virology, Vol. 80, Issue 5 https://doi.org/10.1128/JVI.80.5.2257-2266.2006	journal	February 2006
Requirement of ATM in Phosphorylation of the Human p53 Protein at Serine 15 following DNA Double-Strand Breaks Nakagawa, Kazumi; Taya, Yoichi; Tamai, Katsuyuki Molecular and Cellular Biology, Vol. 19, Issue 4 https://doi.org/10.1128/MCB.19.4.2828	journal	April 1999
Inhibition of p300 Histone Acetyltransferase by Viral Interferon Regulatory Factor Li, M.; Damania, B.; Alvarez, X. Molecular and Cellular Biology, Vol. 20, Issue 21 https://doi.org/10.1128/MCB.20.21.8254-8263.2000	journal	January 2000
Human herpesvirus 8 – A novel human pathogen Edelman, Daniel C. Virology Journal, Vol. 2, Issue 1 https://doi.org/10.1186/1743-422X-2-78	journal	September 2005
Implication of human herpesviruses in oncogenesis through immune evasion and supression Alibek, Kenneth; Baiken, Yeldar; Kakpenova, Ainur Infectious Agents and Cancer, Vol. 9, Issue 1 https://doi.org/10.1186/1750-9378-9-3	journal	January 2014
Structural Basis of Competitive Recognition of p53 and MDM2 by HAUSP/USP7: Implications for the Regulation of the p53–MDM2 Pathway Hu, Min; Gu, Lichuan; Li, Muyang PLoS Biology, Vol. 4, Issue 2 https://doi.org/10.1371/journal.pbio.0040027	journal	January 2006
The Herpesvirus Associated Ubiquitin Specific Protease, USP7, Is a Negative Regulator of PML Proteins and PML Nuclear Bodies Sarkari, Feroz; Wang, Xueqi; Nguyen, Tin PLoS ONE, Vol. 6, Issue 1 https://doi.org/10.1371/journal.pone.0016598	journal	January 2011
Genome-Wide Screen of Three Herpesviruses for Protein Subcellular Localization and Alteration of PML Nuclear Bodies Salsman, Jayme; Zimmerman, Nicole; Chen, Tricia PLoS Pathogens, Vol. 4, Issue 7 https://doi.org/10.1371/journal.ppat.1000100	journal	July 2008
Epstein-Barr Nuclear Antigen 1 Contributes to Nasopharyngeal Carcinoma through Disruption of PML Nuclear Bodies Sivachandran, Nirojini; Sarkari, Feroz; Frappier, Lori PLoS Pathogens, Vol. 4, Issue 10 https://doi.org/10.1371/journal.ppat.1000170	journal	October 2008
Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7 Pfoh, Roland; Lacdao, Ira Kay; Georges, Anna A. PLOS Pathogens, Vol. 11, Issue 6 https://doi.org/10.1371/journal.ppat.1004950	journal	June 2015
Kaposi’s sarcoma-associated herpesvirus and innate immunity West, John A.; Damania, Blossom Future Virology, Vol. 5, Issue 2 https://doi.org/10.2217/fvl.10.5	journal	March 2010
The Viral Interferon Regulatory Factors of KSHV: Immunosuppressors or Oncogenes? Jacobs, Sarah R.; Damania, Blossom Frontiers in Immunology, Vol. 2 https://doi.org/10.3389/fimmu.2011.00019	journal	January 2011

Cited By (9)

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects: Regulatory roles of USP7 Yeasmin Khusbu, Farjana; Chen, Fang-Zhi; Chen, Han-Chun Cell Biochemistry and Function, Vol. 36, Issue 5 https://doi.org/10.1002/cbf.3336	journal	May 2018
Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases Bhattacharya, Seemana; Chakraborty, Dipankar; Basu, Malini Signal Transduction and Targeted Therapy, Vol. 3, Issue 1 https://doi.org/10.1038/s41392-018-0012-y	journal	June 2018
ISG15 in antiviral immunity and beyond Perng, Yi-Chieh; Lenschow, Deborah J. Nature Reviews Microbiology, Vol. 16, Issue 7 https://doi.org/10.1038/s41579-018-0020-5	journal	May 2018
Identification and Characterization of USP7 Targets in Cancer Cells Georges, Anna; Marcon, Edyta; Greenblatt, Jack Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-34197-x	journal	October 2018
USP7 Regulates Cytokinesis through FBXO38 and KIF20B Georges, Anna; Coyaud, Etienne; Marcon, Edyta Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-39368-y	journal	February 2019
The Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA Replication Czech-Sioli, Manja; Siebels, Svenja; Radau, Sonja Journal of Virology, Vol. 94, Issue 5 https://doi.org/10.1128/jvi.01638-19	journal	December 2019
Regulation of the Ebola Virus VP24 Protein by SUMO Vidal, Santiago; El Motiam, Ahmed; Seoane, Rocío Journal of Virology, Vol. 94, Issue 1 https://doi.org/10.1128/jvi.01687-19	journal	October 2019
Human Herpesvirus 8 Interferon Regulatory Factors 1 and 3 Mediate Replication and Latency Activities via Interactions with USP7 Deubiquitinase Xiang, Qiwang; Ju, Hyunwoo; Li, Qian Journal of Virology, Vol. 92, Issue 7 https://doi.org/10.1128/jvi.02003-17	journal	January 2018
The Role of Deubiquitinases in Oncovirus and Host Interactions Li, Yueshuo; Shi, Feng; Hu, Jianmin Journal of Oncology, Vol. 2019 https://doi.org/10.1155/2019/2128410	journal	July 2019

Similar Records

Generation and Validation of Intracellular Ubiquitin Variant Inhibitors for USP7 and USP10

Journal Article · Wed Nov 01 04:00:00 UTC 2017 · Journal of Molecular Biology · OSTI ID:1410112

Zhang, Wei; Sartori, Maria A.; Makhnevych, Taras; +13 more

Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway

Journal Article · Sat Mar 04 04:00:00 UTC 2017 · Biochemical and Biophysical Research Communications · OSTI ID:22696895

Zhan, Meixiao; Sun, Xiaohan; Liu, Jinxiao; +5 more

Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7

Journal Article · Fri Jun 05 00:00:00 UTC 2015 · PLoS Pathogens · OSTI ID:1503690

Pfoh, Roland; Lacdao, Ira Kay; Georges, Anna A.; +5 more

Related Subjects

60 APPLIED LIFE SCIENCES
DNA viruses
KSHV
USP7
X-ray crystallography
deubiquitylation (deubiquitination)
vIRF1
viral protein
virology

Title: Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7

Citation Formats

References (48)

Cited By (9)

Similar Records

Related Subjects