Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 Targets MDM2 To Deregulate the p53 Tumor Suppressor Pathway
Open accessAbstract
Cells infected by viruses utilize interferon (IFN)-mediated and p53-mediated irreversible cell cycle arrest and apoptosis as part of the overall host surveillance mechanism to ultimately block viral replication and dissemination. Viruses, in turn, have evolved elaborate mechanisms to subvert IFN- and p53-mediated host innate immune responses. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several viral IFN regulatory factors (vIRF1 to vIRF4) within a cluster of loci, their functions being primarily to inhibit host IFN-mediated innate immunity and deregulate p53-mediated cell growth control. Despite its significant homology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and antagonize host IFN-mediated signal transduction. Here, we show that KSHV vIRF4 interacts with the murine double minute 2 (MDM2) E3 ubiquitin ligase, leading to the reduction of p53, a tumor suppressor, via proteasome-mediated degradation. The central region of vIRF4 is required for its interaction with MDM2, which led to the suppression of MDM2 autoubiquitination and, thereby, a dramatic increase in MDM2 stability. Consequently, vIRF4 expression markedly enhanced p53 ubiquitination and degradation, effectively suppressing p53-mediated apoptosis. These results indicate that KSHV vIRF4 targets and stabilizes the MDM2 E3 ubiquitin ligase to facilitate the proteasome-mediated degradation of p53, perhaps to circumvent host growth surveillance and facilitate viral replication in infected cells. Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's immune surveillance program against viral infections.
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KSHV expresses vIRF4, a factor that binds MDM2 and seems to switch its ubiquitin ligase activity to p53 degradation.
“Kaposi's sarcoma-associated herpes virus (KSHV) expresses vIRF4, a factor that binds MDM2 and that seems to switch its ubiquitin ligase activity to p53 degradation57.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [57]
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1 retracted
Buschmann, T., Fuchs, S. Y., Lee, C.-G., Pan, Z., & Ronai, Z. A. (2000) · Cell · doi:10.1016/s0092-8674(00)80887-9 · Cited by 267 · see citing works
RetractedIdentification of Herpesvirus-Like DNA Sequences in AIDS-Sssociated Kaposi's Sarcoma
Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M., & Moore, P. S. (1994) · Science · doi:10.1126/science.7997879 · Cited by 5,608 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)
Russo, J. J., Bohenzky, R. A., Chien, M.-C., Chen, J., Yan, M., Maddalena, D., Parry, J. P., Peruzzi, D., Edelman, I. S., Chang, Y., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.25.14862 · Cited by 1,457 · see citing works
Lytic growth of Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8) in culture
Renne, R., Zhong, W., HERNDIER, B. G., et al. (1996) · Nature Medicine · doi:10.1038/nm0396-342 · Cited by 1,046 · see citing works
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044 · see citing works
Modelling the molecular circuitry of cancer
Hahn, W. C., & Weinberg, R. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc795 · Cited by 936 · see citing works
Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2
Li, M., Brooks, C. L., Wu-Baer, F., Chen, D., Baer, R., & Gu, W. (2003) · Science · doi:10.1126/science.1091362 · Cited by 804 · see citing works
Self-citationMoll, U. M., & Petrenko, O. (2003) · PubMed · Cited by 778 · see citing works
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
The MDM2 RING-finger domain is required to promote p53 nuclear export
Geyer, R. K., Yu, Z. K., & Maki, C. G. (2000) · Nature Cell Biology · doi:10.1038/35023507 · Cited by 361 · see citing works
Nakamura, H., Lu, M., Gwack, Y., Souvlis, J., Zeichner, S. L., & Jung, J. U. (2003) · Journal of Virology · doi:10.1128/jvi.77.7.4205-4220.2003 · Cited by 300 · see citing works
Self-citationRivas, C., Thlick, A.-E., Parravicini, C., Moore, P. S., & Chang, Y. (2001) · Journal of Virology · doi:10.1128/jvi.75.1.429-438.2001 · Cited by 296 · see citing works
Feng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404936200 · Cited by 294 · see citing works
The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
Stevenson, L. F., Sparks, A., Allende‐Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601567 · Cited by 280 · see citing works
Meulmeester, E., Maurice, M. M., Boutell, C., Teunisse, A. F. A. S., Ovaa, H., Abraham, T. E., Dirks, R. W., & Jochemsen, A. G. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.024 · Cited by 260 · see citing works
Katano, H., Sato, Y., Kurata, T., et al. (2000) · Virology · doi:10.1006/viro.2000.0196 · Cited by 254 · see citing works
Mechanisms of switching on p53: a role for covalent modification?
Meek, D. W. (1999) · Oncogene · doi:10.1038/sj.onc.1202951 · Cited by 235 · see citing works
Kaposi's Sarcoma–Associated Herpesvirus Immunoevasion and Tumorigenesis: Two Sides of the Same Coin?
Moore, P. S., & Chang, Y. (2003) · Annual Review of Microbiology · doi:10.1146/annurev.micro.57.030502.090824 · Cited by 221 · see citing works
Burýšek, L., Yeow, W.-S., Lubyová, B., Kellum, M. J., Schafer, S. L., Huang, Y. Q., & Pitha, P. M. (1999) · Journal of Virology · doi:10.1128/jvi.73.9.7334-7342.1999 · Cited by 212 · see citing works
Lin, R., Génin, P., Mamane, Y., Sgarbanti, M., Battistini, A., Harrington, W. J., Barber, G. N., & Hiscott, J. B. (2001) · Oncogene · doi:10.1038/sj.onc.1204163 · Cited by 212 · see citing works
Kaposi’s Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor
Li, M., Lee, H., Guo, J., Neipel, F., Ozato, K., Jung, J. U., Fleckenstein, B., Jae, & Jung, U. (1997) · Cited by 171 · see citing works
Self-citationImmune evasion by Kaposi's sarcoma-associated herpesvirus
Coscoy, L. (2007) · Nature reviews. Immunology · doi:10.1038/nri2076 · Cited by 151 · see citing works
Kaposi’s Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor
Li, M., Lee, H., Guo, J., Neipel, F., Fleckenstein, B., Ozato, K., & Jung, J. U. (1998) · Journal of Virology · doi:10.1128/jvi.72.7.5433-5440.1998 · Cited by 151 · see citing works
Self-citationMolecular virology of Kaposi's sarcoma–associated herpesvirus
Moore, P. S., & Chang, Y. (2001) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2000.0777 · Cited by 147 · see citing works
The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP
Brooks, C. L., Li, M., Hu, M., Shi, Y., & Gu, W. (2007) · Oncogene · doi:10.1038/sj.onc.1210531 · Cited by 144 · see citing works
Self-citationKaposi's sarcoma-associated herpesvirus immune modulation: an overview
Rezaee, S. A., Cunningham, C., Davison, A. J., & Blackbourn, D. J. (2006) · Journal of General Virology · doi:10.1099/vir.0.81919-0 · Cited by 144 · see citing works
Joo, C. H., Shin, Y. C., Gack, M. U., Wu, L., Levy, D. E., & Jung, J. U. (2007) · Journal of Virology · doi:10.1128/jvi.00235-07 · Cited by 142 · see citing works
Self-citationShin, Y. C., Nakamura, H., Liang, X., Feng, P., Chang, H., Kowalik, T. F., & Jung, J. U. (2006) · Journal of Virology · doi:10.1128/jvi.80.5.2257-2266.2006 · Cited by 136 · see citing works
Self-citationSeo, T., Park, J., Lee, D., Hwang, S. G., & Choe, J. (2001) · Journal of Virology · doi:10.1128/jvi.75.13.6193-6198.2001 · Cited by 121 · see citing works
Fuld, S., Cunningham, C., Klucher, K. M., Davison, A. J., & Blackbourn, D. J. (2006) · Journal of Virology · doi:10.1128/jvi.80.6.3092-3097.2006 · Cited by 100 · see citing works
Unleashing the power of p53: lessons from mice and men: Figure 1.Preprint
Poyurovsky, M. V., & Prives, C. L. (2006) · Genes & Development · doi:10.1101/gad.1397506 · Cited by 96 · see citing works
Stommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 87 · see citing works
Transcription mapping of human herpesvirus 8 genes encoding viral interferon regulatory factors
Cunningham, C., Barnard, S., Blackbourn, D. J., & Davison, A. J. (2003) · Journal of General Virology · doi:10.1099/vir.0.19015-0 · Cited by 77 · see citing works
Regulation of p53 and MDM2 Activity by MTBP
Brady, M., Vlatković, N., & Boyd, M. T. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.2.545-553.2005 · Cited by 69 · see citing works
Human tumor suppressor p53 and DNA viruses
Collot-Teixeira, S., Bass, J., Denis, F., & Ranger‐Rogez, S. (2004) · Reviews in Medical Virology · doi:10.1002/rmv.431 · Cited by 67 · see citing works
Structural Analysis of the Kaposi's Sarcoma-Associated Herpesvirus K1 Protein
Lee, B.-S., Connole, M., Tang, Z., et al. (2003) · Journal of Virology · doi:10.1128/jvi.77.14.8072-8086.2003 · Cited by 54 · see citing works
Kaposi Sarcoma Herpesvirus-Encoded Interferon Regulator Factors
Offermann, M. K. (2006) · Springer eBooks · doi:10.1007/978-3-540-34344-8_7 · Cited by 51 · see citing works
Kanno, T., Sato, Y., Sata, T., et al. (2006) · Virology · doi:10.1016/j.virol.2006.04.009 · Cited by 33 · see citing works
The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability
D’Arcy, P., Maruwge, W., Ryan, B. A., & Brodin, B. A. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-0176 · Cited by 32 · see citing works
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Research works printed but not linked: 1
- [34]Prives, C., and P. A. Hall. 1999. The p53 pathway. J. Pathol. 187112-126. [DOI] [PubMed] [Google Scholar]
Cited by
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MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
- Authors
- Lee, H.-R., Toth, Z., Shin, Y. C., Lee, J.-S., Chang, H., Gu, W., Oh, T.-K., Kim, M. H., & Jung, J. U.
- Affiliations
- University of Southern California (US)
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, California 90033
- Harvard University (US)
- Columbia University (US)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Jung, Jae U.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2009-07
- Volume
- 83
- Issue
- 13
- Pages
- 6739-6747
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC2698538
- OpenAlex
- W2124781791
- Cited by
- 78
- References
- 43
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 2 · 2013: 9 · 2012: 6
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KRIBB Repository (submittedVersion)
- Funders
- National Cancer Institute (CA082057, R01CA082057, CA115284, R01CA115284)
- National Institute of Dental and Craniofacial Research (P01DE019085, DE019085)
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- Kaposi's sarcoma-associated herpesvirus, MDM2, p53, p53 degradation, viral immune evasion, host innate immunity, apoptosis, viral oncogenesis, host-virus interaction
- MeSH terms
- Cell Line, Gene Expression Regulation, Humans, Repressor Proteins, Viral Proteins, Down-Regulation, Tumor Suppressor Protein p53, Apoptosis, Herpesvirus 8, Human, Interferon Regulatory Factors, Proto-Oncogene Proteins c-mdm2, Ubiquitination
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