USP11對EB病毒Rta及Zta的泛素化所扮演的角色

Role of USP11 in the ubiquitination of Rta and Zta of Epstein-Barr Virus

10.6342/NTU201703614

陳紀元

EB 病毒 ； Rta ； Zta ； USP11 ； 去泛素化 ； Epstein-Barr Virus ； Rta ； Zta ； USP11 ； deubiquitination

臺灣大學生化科技學系學位論文

2017年

碩士

張麗冠

繁體中文

EB病毒（Epstein-Barr Virus）是一種廣泛感染人類的雙股DNA致癌病毒，其生活史分為潛伏期（lysogenic cycle）和溶裂期（lytic cycle），病毒在進入溶裂期時需要Rta和Zta這兩種極早期蛋白質。Rta和Zta 主要作為病毒的轉錄活化因子（transactivator），會透過細胞中的RanBPM進行協同活化（synergistic activation）以幫助活化早期基因使病毒能進行大量的複製。本實驗室先前證實了Rta會被細胞內的一種SUMO-targeted ubiquitin E3 ligase，RNF4，進行泛素化修飾（ubiquitin modification）之後再被降解，因而抑制溶裂期的進展。而USP11是一種會與RNF4拮抗的去泛素化酶（deubiquitinase），本研究室未發表的結果發現USP11可能參與Zta降低Rta的泛素化修飾。本研究透過不會被泛素化的Zta突變蛋白質ZK12R，證明了Zta是利用USP11降低Rta的泛素化修飾而非透過對泛素的競爭。之後以活性突變的USP11蛋白質驗證了USP11 是Rta的去泛素化酶。然後透過抑制基因表現（knockdown）的方式分別確認RanBPM和USP11皆會影響Rta的泛素化修飾，而Zta泛素化修飾則是受USP11影響較大。另外，利用同時過量表現USP11和抑制RanBPM基因表現的方式，驗證了USP11降低Rta泛素化修飾需要有RanBPM參與其中，但是在同時表現Zta和抑制RanBPM表現的情況中，則觀察到RanBPM在Zta降低Rta泛素化修飾的機制中並不是必要的。最後利用穩定抑制USP11表現的P3HR1細胞株，證明缺少USP11會些微抑制溶裂期的進行。綜合以上，本研究發現Zta可以透過細胞內的USP11降低Rta的泛素化修飾，進而穩定Rta，因此有利EB病毒的複製增殖。

Epstein-Barr virus is a double stranded DNA oncovirus. The life cycle of EBV can be separated into latent and lytic cycles. The immediate-early proteins, Rta and Zta are necessary for EBV lytic cycle development. They both are viral transactivators that can synergistically activate viral early genes through RanBPM to facilitate viral DNA replication. Our previous study demonstrates that Rta was ubiquitinated by RNF4, a SUMO-targeted ubiquitin E3 ligase, thereby inhibiting lytic progression. Moreover, USP11, a deubiquitinase, has been shown to counteract the functions of RNF4. Our results also suggest that USP11 participates in the reduction of Rta’s ubiquitination by Zta. Firstly, this study showed that Zta utilized USP11 to reduce the amounts of ubiquitinated Rta, but not through the competition of ubiquitins by using ZK12R, a Zta sumoylation-defective mutant. This study further demonstrated by using a catalytic mutant of USP11 that USP11 is a deubiquitinase of Rta. Moreover, the experiments of gene knockdown confirmed that the ubiquitination of Rta is affected by USP11 and RanBPM. However, Zta’s ubiquitination depends on USP11. Meanwhile, the deubiquitination of Rta by USP11 requires the participation of RanBPM since downregulation of RanBPM inhibites USP11-mediated deubiquitination of Rta. Although RanBPM is necessary in the USP11-mediated Rta deubiquitination, this study found that Zta is able to decrease Rta’s ubiquitination when RanBPM is knocked down by shRNA. This study also showed that EBV lytic cycle was repressed in P3HR1 cells with USP11 silencing. Altogether, this study reveals that Zta is involved in the USP11-mediated deubiquitination of Rta to stabilize Rta to promote EBV lytic development.

1. 楊雅君 (2013) 泛素化修飾與EB病毒Rta及Zta的協同作用. 國立臺灣大學生命科學院生化科技學系博士論文.
   連結：
2. Adamson, A. L. & S. Kenney (2001) Epstein-barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies. J Virol, 75, 2388-99.
   連結：
3. Bar, R. S., C. J. DeLor, K. P. Clausen, P. Hurtubise, W. Henle & J. F. Hewetson (1974) Fatal infectious mononucleosis in a family. N Engl J Med, 290, 363-7.
   連結：
4. Bertani, G. (1951) Studies on lysogenesis. I. The mode of phage liberation by lysogenic Escherichia coli. J Bacteriol, 62, 293-300.
   連結：
5. Bhende, P. M., W. T. Seaman, H. J. Delecluse & S. C. Kenney (2004) The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet, 36, 1099-104.
   連結：
6. Burkhart, R. A., Y. Peng, Z. A. Norris, R. M. Tholey, V. A. Talbott, Q. Liang, Y. Ai, K. Miller, S. Lal, J. A. Cozzitorto, A. K. Witkiewicz, C. J. Yeo, M. Gehrmann, A. Napper, J. M. Winter, J. A. Sawicki, Z. Zhuang & J. R. Brody (2013) Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. Mol Cancer Res, 11, 901-11.
   連結：
7. Chang, L. K., J. Y. Chuang, M. Nakao & S. T. Liu (2010) MCAF1 and synergistic activation of the transcription of Epstein-Barr virus lytic genes by Rta and Zta. Nucleic Acids Res, 38, 4687-700.
   連結：
8. Chang, L. K., J. Y. Chung, Y. R. Hong, T. Ichimura, M. Nakao & S. T. Liu (2005) Activation of Sp1-mediated transcription by Rta of Epstein-Barr virus via an interaction with MCAF1. Nucleic Acids Res, 33, 6528-39.
   連結：
9. Chang, L. K., Y. H. Lee, T. S. Cheng, Y. R. Hong, P. J. Lu, J. J. Wang, W. H. Wang, C. W. Kuo, S. S. Li & S. T. Liu (2004) Post-translational modification of Rta of Epstein-Barr virus by SUMO-1. J Biol Chem, 279, 38803-12.
   連結：
10. Chang, L. K., S. T. Liu, C. W. Kuo, W. H. Wang, J. Y. Chuang, E. Bianchi & Y. R. Hong (2008) Enhancement of transactivation activity of Rta of Epstein-Barr virus by RanBPM. J Mol Biol, 379, 231-42.
    連結：
11. Chiu, Y. F., A. U. Sugden & B. Sugden (2013) Epstein-Barr viral productive amplification reprograms nuclear architecture, DNA replication, and histone deposition. Cell Host Microbe, 14, 607-18.
    連結：
12. Daubeuf, S., D. Singh, Y. Tan, H. Liu, H. J. Federoff, W. J. Bowers & K. Tolba (2009) HSV ICP0 recruits USP7 to modulate TLR-mediated innate response. Blood, 113, 3264-75.
    連結：
13. Denti, S., A. Sirri, A. Cheli, L. Rogge, G. Innamorati, S. Putignano, M. Fabbri, R. Pardi & E. Bianchi (2004) RanBPM is a phosphoprotein that associates with the plasma membrane and interacts with the integrin LFA-1. J Biol Chem, 279, 13027-34.
    連結：
14. Epstein, M. A., B. G. Achong & Y. M. Barr (1964) Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma. Lancet, 1, 702-3.
    連結：
15. Feederle, R., M. Kost, M. Baumann, A. Janz, E. Drouet, W. Hammerschmidt & H. J. Delecluse (2000) The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J, 19, 3080-9.
    連結：
16. Flemington, E. & S. H. Speck (1990b) Evidence for coiled-coil dimer formation by an Epstein-Barr virus transactivator that lacks a heptad repeat of leucine residues. Proc Natl Acad Sci U S A, 87, 9459-63.
    連結：
17. Flemington, E. K., J. P. Lytle, C. Cayrol, A. M. Borras & S. H. Speck (1994) DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities. Mol Cell Biol, 14, 3041-52.
    連結：
18. Gack, M. U., Y. C. Shin, C. H. Joo, T. Urano, C. Liang, L. Sun, O. Takeuchi, S. Akira, Z. Chen, S. Inoue & J. U. Jung (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature, 446, 916-920.
    連結：
19. Graham, F. L., J. Smiley, W. C. Russell & R. Nairn (1977) Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol, 36, 59-74.
    連結：
20. Greene, W., W. Zhang, M. He, C. Witt, F. Ye & S. J. Gao (2012) The ubiquitin/proteasome system mediates entry and endosomal trafficking of Kaposi's sarcoma-associated herpesvirus in endothelial cells. PLoS Pathog, 8, e1002703.
    連結：
21. Gruffat, H., E. Manet, A. Rigolet & A. Sergeant (1990) The enhancer factor R of Epstein-Barr virus (EBV) is a sequence-specific DNA binding protein. Nucleic Acids Res, 18, 6835-43.
    連結：
22. Harper, S., H. E. Gratton, I. Cornaciu, M. Oberer, D. J. Scott, J. Emsley & I. Dreveny (2014) Structure and catalytic regulatory function of ubiquitin specific protease 11 N-terminal and ubiquitin-like domains. Biochemistry, 53, 2966-78.
    連結：
23. Hendriks, I. A., J. Schimmel, K. Eifler, J. V. Olsen & A. C. Vertegaal (2015) Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4). J Biol Chem, 290, 15526-37.
    連結：
24. Henle, W. & G. Henle (1970) Evidence for a relation of Epstein-Barr virus to Burkitt's lymphoma and nasopharyngeal carcinoma. Bibl Haematol, 706-13.
    連結：
25. Hershko, A. & A. Ciechanover (1992) The ubiquitin system for protein degradation. Annu Rev Biochem, 61, 761-807.
    連結：
26. Hershko, A. & A. Ciechanover (1998) The ubiquitin system. Annu Rev Biochem, 67, 425-79.
    連結：
27. Hershko, A., A. Ciechanover, H. Heller, A. L. Haas & I. A. Rose (1980) Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc Natl Acad Sci U S A, 77, 1783-6.
    連結：
28. Heston, L., M. Rabson, N. Brown & G. Miller (1982) New Epstein-Barr virus variants from cellular subclones of P3J-HR-1 Burkitt lymphoma. Nature, 295, 160-3.
    連結：
29. Hettich, E., A. Janz, R. Zeidler, D. Pich, E. Hellebrand, B. Weissflog, A. Moosmann & W. Hammerschmidt (2006) Genetic design of an optimized packaging cell line for gene vectors transducing human B cells. Gene Ther, 13, 844-56.
    連結：
30. Hoege, C., B. Pfander, G. L. Moldovan, G. Pyrowolakis & S. Jentsch (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature, 419, 135-41.
    連結：
31. Holowaty, M. N. & L. Frappier (2004) HAUSP/USP7 as an Epstein-Barr virus target. Biochem Soc Trans, 32, 731-2.
    連結：
32. Hosono, K., S. Noda, A. Shimizu, N. Nakanishi, M. Ohtsubo, N. Shimizu & S. Minoshima (2010) YPEL5 protein of the YPEL gene family is involved in the cell cycle progression by interacting with two distinct proteins RanBPM and RanBP10. Genomics, 96, 102-11.
    連結：
33. Hu, M., P. Li, M. Li, W. Li, T. Yao, J. W. Wu, W. Gu, R. E. Cohen & Y. Shi (2002) Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell, 111, 1041-54.
    連結：
34. Huang, H. H., C. S. Chen, W. H. Wang, S. W. Hsu, H. H. Tsai, S. T. Liu & L. K. Chang (2016) TRIM5alpha Promotes Ubiquitination of Rta from Epstein-Barr Virus to Attenuate Lytic Progression. Front Microbiol, 7, 2129.
    連結：
35. Humme, S., G. Reisbach, R. Feederle, H. J. Delecluse, K. Bousset, W. Hammerschmidt & A. Schepers (2003) The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci U S A, 100, 10989-94.
    連結：
36. Ideguchi, H., A. Ueda, M. Tanaka, J. Yang, T. Tsuji, S. Ohno, E. Hagiwara, A. Aoki & Y. Ishigatsubo (2002) Structural and functional characterization of the USP11 deubiquitinating enzyme, which interacts with the RanGTP-associated protein RanBPM. Biochem J, 367, 87-95.
    連結：
37. Ikeda, M., A. Ikeda, L. C. Longan & R. Longnecker (2000) The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases. Virology, 268, 178-91.
    連結：
38. Inn, K. S., S. H. Lee, J. Y. Rathbun, L. Y. Wong, Z. Toth, K. Machida, J. H. Ou & J. U. Jung (2011) Inhibition of RIG-I-mediated signaling by Kaposi's sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J Virol, 85, 10899-904.
    連結：
39. Isaacson, M. K. & H. L. Ploegh (2009) Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe, 5, 559-70.
    連結：
40. Israel, B. F. & S. C. Kenney (2003) Virally targeted therapies for EBV-associated malignancies. Oncogene, 22, 5122-30.
    連結：
41. Johansson, B., G. Klein, W. Henle & G. Henle (1970) Epstein-Barr virus (EBV)-associated antibody patterns in malignant lymphoma and leukemia. I. Hodgkin's disease. Int J Cancer, 6, 450-62.
    連結：
42. Kane, L. A., M. Lazarou, A. I. Fogel, Y. Li, K. Yamano, S. A. Sarraf, S. Banerjee & R. J. Youle (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol, 205, 143-53.
    連結：
43. Kim, T., S. Kim, H. M. Yun, K. C. Chung, Y. S. Han, H. S. Shin & H. Rhim (2009) Modulation of Ca(v)3.1 T-type Ca2+ channels by the ran binding protein RanBPM. Biochem Biophys Res Commun, 378, 15-20.
    連結：
44. Komander, D., M. J. Clague & S. Urbe (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol, 10, 550-63.
    連結：
45. Kramer, S., T. Ozaki, K. Miyazaki, C. Kato, T. Hanamoto & A. Nakagawara (2005) Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells. Oncogene, 24, 938-44.
    連結：
46. Kumar, R., C. B. Whitehurst & J. S. Pagano (2014) The Rad6/18 ubiquitin complex interacts with the Epstein-Barr virus deubiquitinating enzyme, BPLF1, and contributes to virus infectivity. J Virol, 88, 6411-22.
    連結：
47. Lakshmana, M. K., I. S. Yoon, E. Chen, E. Bianchi, E. H. Koo & D. E. Kang (2009) Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation. J Biol Chem, 284, 11863-72.
    連結：
48. Lamoliatte, F., E. Bonneil, C. Durette, O. Caron-Lizotte, D. Wildemann, J. Zerweck, H. Wenshuk & P. Thibault (2013) Targeted identification of SUMOylation sites in human proteins using affinity enrichment and paralog-specific reporter ions. Mol Cell Proteomics, 12, 2536-50.
    連結：
49. Lee, H. R., Z. Toth, Y. C. Shin, J. S. Lee, H. Chang, W. Gu, T. K. Oh, M. H. Kim & J. U. Jung (2009) Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J Virol, 83, 6739-47.
    連結：
50. Li, Y., J. Webster-Cyriaque, C. C. Tomlinson, M. Yohe & S. Kenney (2004) Fatty acid synthase expression is induced by the Epstein-Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. J Virol, 78, 4197-206.
    連結：
51. Liao, T. L., C. Y. Wu, W. C. Su, K. S. Jeng & M. M. Lai (2010) Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication. EMBO J, 29, 3879-90.
    連結：
52. Lim, K. H., B. Suresh, J. H. Park, Y. S. Kim, S. Ramakrishna & K. H. Baek (2016) Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth. Oncotarget, 7, 14441-57.
    連結：
53. Lin, C. H., H. S. Chang & W. C. Yu (2008) USP11 stabilizes HPV-16E7 and further modulates the E7 biological activity. J Biol Chem, 283, 15681-8.
    連結：
54. Lin, T. Y., Y. Y. Chu, Y. C. Yang, S. W. Hsu, S. T. Liu & L. K. Chang (2014) MCAF1 and Rta-activated BZLF1 transcription in Epstein-Barr virus. PLoS One, 9, e90698.
    連結：
55. Lindahl, T., A. Adams, G. Bjursell, G. W. Bornkamm, C. Kaschka-Dierich & U. Jehn (1976) Covalently closed circular duplex DNA of Epstein-Barr virus in a human lymphoid cell line. J Mol Biol, 102, 511-30.
    連結：
56. Liu, S., A. M. Borras, P. Liu, G. Suske & S. H. Speck (1997) Binding of the ubiquitous cellular transcription factors Sp1 and Sp3 to the ZI domains in the Epstein-Barr virus lytic switch BZLF1 gene promoter. Virology, 228, 11-8.
    連結：
57. Luka, J., B. Kallin & G. Klein (1979) Induction of the Epstein-Barr virus (EBV) cycle in latently infected cells by n-butyrate. Virology, 94, 228-31.
    連結：
58. Mahot, S., A. Sergeant, E. Drouet & H. Gruffat (2003) A novel function for the Epstein-Barr virus transcription factor EB1/Zta: induction of transcription of the hIL-10 gene. J Gen Virol, 84, 965-74.
    連結：
59. Manet, E., A. Rigolet, H. Gruffat, J. F. Giot & A. Sergeant (1991) Domains of the Epstein-Barr virus (EBV) transcription factor R required for dimerization, DNA binding and activation. Nucleic Acids Res, 19, 2661-7.
    連結：
60. Mauser, A., E. Holley-Guthrie, D. Simpson, W. Kaufmann & S. Kenney (2002) The Epstein-Barr virus immediate-early protein BZLF1 induces both a G(2) and a mitotic block. J Virol, 76, 10030-7.
    連結：
61. Mettenleiter, T. C. (2002) Herpesvirus Assembly and Egress. Journal of Virology, 76, 1537-1547.
    連結：
62. Mettenleiter, T. C. (2004) Budding events in herpesvirus morphogenesis. Virus Res, 106, 167-80.
    連結：
63. Miller, G. (1990) The switch between latency and replication of Epstein-Barr virus. J Infect Dis, 161, 833-44.
    連結：
64. Morrison, T. E. & S. C. Kenney (2004) BZLF1, an Epstein-Barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function. Virology, 328, 219-32.
    連結：
65. Morrison, T. E., A. Mauser, A. Klingelhutz & S. C. Kenney (2004) Epstein-Barr virus immediate-early protein BZLF1 inhibits tumor necrosis factor alpha-induced signaling and apoptosis by downregulating tumor necrosis factor receptor 1. J Virol, 78, 544-9.
    連結：
66. Neuhierl, B. & H. J. Delecluse (2006) The Epstein-Barr virus BMRF1 gene is essential for lytic virus replication. J Virol, 80, 5078-81.
    連結：
67. Niederman, J. C. & G. Miller (1986) Kinetics of the antibody response to BamHI-K nuclear antigen in uncomplicated infectious mononucleosis. J Infect Dis, 154, 346-9.
    連結：
68. Nijman, S. M., M. P. Luna-Vargas, A. Velds, T. R. Brummelkamp, A. M. Dirac, T. K. Sixma & R. Bernards (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell, 123, 773-86.
    連結：
69. Ning, S. & J. S. Pagano (2010) The A20 deubiquitinase activity negatively regulates LMP1 activation of IRF7. J Virol, 84, 6130-8.
    連結：
70. Nishitani, H., E. Hirose, Y. Uchimura, M. Nakamura, M. Umeda, K. Nishii, N. Mori & T. Nishimoto (2001) Full-sized RanBPM cDNA encodes a protein possessing a long stretch of proline and glutamine within the N-terminal region, comprising a large protein complex. Gene, 272, 25-33.
    連結：
71. Odumade, O. A., K. A. Hogquist & H. H. Balfour, Jr. (2011) Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev, 24, 193-209.
    連結：
72. Ohtake, F., Y. Saeki, K. Sakamoto, K. Ohtake, H. Nishikawa, H. Tsuchiya, T. Ohta, K. Tanaka & J. Kanno (2015) Ubiquitin acetylation inhibits polyubiquitin chain elongation. EMBO Rep, 16, 192-201.
    連結：
73. Ovaa, H., B. M. Kessler, U. Rolen, P. J. Galardy, H. L. Ploegh & M. G. Masucci (2004) Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci U S A, 101, 2253-8.
    連結：
74. Peloponese, J. M., Jr., H. Iha, V. R. Yedavalli, A. Miyazato, Y. Li, K. Haller, M. Benkirane & K. T. Jeang (2004) Ubiquitination of human T-cell leukemia virus type 1 tax modulates its activity. J Virol, 78, 11686-95.
    連結：
75. Peng, J., D. Schwartz, J. E. Elias, C. C. Thoreen, D. Cheng, G. Marsischky, J. Roelofs, D. Finley & S. P. Gygi (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol, 21, 921-6.
    連結：
76. Precious, B., K. Childs, V. Fitzpatrick-Swallow, S. Goodbourn & R. E. Randall (2005) Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate the ubiquitination of STAT1. J Virol, 79, 13434-41.
    連結：
77. Quinlivan, E. B., E. A. Holley-Guthrie, M. Norris, D. Gutsch, S. L. Bachenheimer & S. C. Kenney (1993) Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Nucleic Acids Res, 21, 1999-2007.
    連結：
78. Ragoczy, T. & G. Miller (2001) Autostimulation of the Epstein-Barr virus BRLF1 promoter is mediated through consensus Sp1 and Sp3 binding sites. J Virol, 75, 5240-51.
    連結：
79. Rao, M. A., H. Cheng, A. N. Quayle, H. Nishitani, C. C. Nelson & P. S. Rennie (2002) RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid receptor. J Biol Chem, 277, 48020-7.
    連結：
80. Sarisky, R. T., Z. Gao, P. M. Lieberman, E. D. Fixman, G. S. Hayward & S. D. Hayward (1996) A replication function associated with the activation domain of the Epstein-Barr virus Zta transactivator. J Virol, 70, 8340-7.
    連結：
81. Sarkari, F., T. Sanchez-Alcaraz, S. Wang, M. N. Holowaty, Y. Sheng & L. Frappier (2009) EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein-Barr virus latent origin of DNA replication. PLoS Pathog, 5, e1000624.
    連結：
82. Satheshkumar, P. S., L. C. Anton, P. Sanz & B. Moss (2009) Inhibition of the ubiquitin-proteasome system prevents vaccinia virus DNA replication and expression of intermediate and late genes. J Virol, 83, 2469-79.
    連結：
83. Scheffner, M., B. A. Werness, J. M. Huibregtse, A. J. Levine & P. M. Howley (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63, 1129-36.
    連結：
84. Schoenfeld, A. R., S. Apgar, G. Dolios, R. Wang & S. A. Aaronson (2004) BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol, 24, 7444-55.
    連結：
85. Sharma, N., Q. Zhu, G. Wani, J. He, Q. E. Wang & A. A. Wani (2014) USP3 counteracts RNF168 via deubiquitinating H2A and gammaH2AX at lysine 13 and 15. Cell Cycle, 13, 106-14.
    連結：
86. Shaw, G., S. Morse, M. Ararat & F. L. Graham (2002) Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. FASEB J, 16, 869-71.
    連結：
87. Singh, R. K., S. Zerath, O. Kleifeld, M. Scheffner, M. H. Glickman & D. Fushman (2012) Recognition and cleavage of related to ubiquitin 1 (Rub1) and Rub1-ubiquitin chains by components of the ubiquitin-proteasome system. Mol Cell Proteomics, 11, 1595-611.
    連結：
88. Strack, B., A. Calistri, M. A. Accola, G. Palu & H. G. Gottlinger (2000) A role for ubiquitin ligase recruitment in retrovirus release. Proc Natl Acad Sci U S A, 97, 13063-8.
    連結：
89. Strayhorn, W. D. & B. E. Wadzinski (2002) A novel in vitro assay for deubiquitination of I kappa B alpha. Arch Biochem Biophys, 400, 76-84.
    連結：
90. Suresh, B., S. Ramakrishna, Y. S. Kim, S. M. Kim, M. S. Kim & K. H. Baek (2010) Stability and function of mammalian lethal giant larvae-1 oncoprotein are regulated by the scaffolding protein RanBPM. J Biol Chem, 285, 35340-9.
    連結：
91. Teale, A., S. Campbell, N. Van Buuren, W. C. Magee, K. Watmough, B. Couturier, R. Shipclark & M. Barry (2009) Orthopoxviruses require a functional ubiquitin-proteasome system for productive replication. J Virol, 83, 2099-108.
    連結：
92. Vijay-Kumar, S., C. E. Bugg & W. J. Cook (1987) Structure of ubiquitin refined at 1.8 A resolution. J Mol Biol, 194, 531-44.
    連結：
93. Wang, C., L. Deng, M. Hong, G. R. Akkaraju, J. Inoue & Z. J. Chen (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 412, 346-51.
    連結：
94. Wertz, I. E., K. M. O'Rourke, H. Zhou, M. Eby, L. Aravind, S. Seshagiri, P. Wu, C. Wiesmann, R. Baker, D. L. Boone, A. Ma, E. V. Koonin & V. M. Dixit (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature, 430, 694-9.
    連結：
95. Whitehurst, C. B., S. Ning, G. L. Bentz, F. Dufour, E. Gershburg, J. Shackelford, Y. Langelier & J. S. Pagano (2009) The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity. J Virol, 83, 4345-53.
    連結：
96. Winberg, G., L. Matskova, F. Chen, P. Plant, D. Rotin, G. Gish, R. Ingham, I. Ernberg & T. Pawson (2000) Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases. Mol Cell Biol, 20, 8526-35.
    連結：
97. Wu, F. Y., H. Chen, S. E. Wang, C. M. ApRhys, G. Liao, M. Fujimuro, C. J. Farrell, J. Huang, S. D. Hayward & G. S. Hayward (2003) CCAAT/enhancer binding protein alpha interacts with ZTA and mediates ZTA-induced p21(CIP-1) accumulation and G(1) cell cycle arrest during the Epstein-Barr virus lytic cycle. J Virol, 77, 1481-500.
    連結：
98. Yamaguchi, T., J. Kimura, Y. Miki & K. Yoshida (2007) The deubiquitinating enzyme USP11 controls an IkappaB kinase alpha (IKKalpha)-p53 signaling pathway in response to tumor necrosis factor alpha (TNFalpha). J Biol Chem, 282, 33943-8.
    連結：
99. Yang, Y. C. & L. K. Chang (2013) Role of TAF4 in transcriptional activation by Rta of Epstein-Barr Virus. PLoS One, 8, e54075.
    連結：
100. Yang, Y. C., T. H. Feng, T. Y. Chen, H. H. Huang, C. C. Hung, S. T. Liu & L. K. Chang (2015) RanBPM regulates Zta-mediated transcriptional activity in Epstein-Barr virus. J Gen Virol, 96, 2336-48.
     連結：
101. Yang, Y. C., Y. Yoshikai, S. W. Hsu, H. Saitoh & L. K. Chang (2013) Role of RNF4 in the ubiquitination of Rta of Epstein-Barr virus. J Biol Chem, 288, 12866-79.
     連結：
102. Yaron, A., A. Hatzubai, M. Davis, I. Lavon, S. Amit, A. M. Manning, J. S. Andersen, M. Mann, F. Mercurio & Y. Ben-Neriah (1998) Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature, 396, 590-4.
     連結：
103. Yu, Y., S. E. Wang & G. S. Hayward (2005) The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity, 22, 59-70.
     連結：
104. Yuan, Y., C. Fu, H. Chen, X. Wang, W. Deng & B. R. Huang (2006) The Ran binding protein RanBPM interacts with TrkA receptor. Neurosci Lett, 407, 26-31.
     連結：
105. Zhou, H., I. Wertz, K. O'Rourke, M. Ultsch, S. Seshagiri, M. Eby, W. Xiao & V. M. Dixit (2004) Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature, 427, 167-71.
     連結：
106. zur Hausen, H., F. J. O'Neill, U. K. Freese & E. Hecker (1978) Persisting oncogenic herpesvirus induced by the tumour promotor TPA. Nature, 272, 373-5.
     連結：
107. Biggin, M., M. Bodescot, M. Perricaudet & P. Farrell (1987) Epstein-Barr virus gene expression in P3HR1-superinfected Raji cells. J Virol, 61, 3120-32.
108. Cayrol, C. & E. K. Flemington (1995) Identification of cellular target genes of the Epstein-Barr virus transactivator Zta: activation of transforming growth factor beta igh3 (TGF-beta igh3) and TGF-beta 1. J Virol, 69, 4206-12.
109. Chang, P. J., Y. S. Chang & S. T. Liu (1998) Role of Rta in the translation of bicistronic BZLF1 of Epstein-Barr virus. J Virol, 72, 5128-36.
110. Davies, A. H., R. J. Grand, F. J. Evans & A. B. Rickinson (1991) Induction of Epstein-Barr virus lytic cycle by tumor-promoting and non-tumor-promoting phorbol esters requires active protein kinase C. J Virol, 65, 6838-44.
111. Durcan, T. M., M. Y. Tang, J. R. Perusse, E. A. Dashti, M. A. Aguileta, G. L. McLelland, P. Gros, T. A. Shaler, D. Faubert, B. Coulombe & E. A. Fon (2014) USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. The EMBO Journal, 33, 2473-2491.
112. Farrell, P. J., D. T. Rowe, C. M. Rooney & T. Kouzarides (1989) Epstein-Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J, 8, 127-32.
113. Fixman, E. D., G. S. Hayward & S. D. Hayward (1995) Replication of Epstein-Barr virus oriLyt: lack of a dedicated virally encoded origin-binding protein and dependence on Zta in cotransfection assays. J Virol, 69, 2998-3006.
114. Flemington, E. & S. H. Speck (1990a) Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol, 64, 1227-32.
115. Flemington, E. K., A. M. Borras, J. P. Lytle & S. H. Speck (1992) Characterization of the Epstein-Barr virus BZLF1 protein transactivation domain. J Virol, 66, 922-9.
116. Hardwick, J. M., L. Tse, N. Applegren, J. Nicholas & M. A. Veliuona (1992) The Epstein-Barr virus R transactivator (Rta) contains a complex, potent activation domain with properties different from those of VP16. J Virol, 66, 5500-8.
117. Hinuma, Y., M. Konn, J. Yamaguchi, D. J. Wudarski, J. R. Blakeslee, Jr. & J. T. Grace, Jr. (1967) Immunofluorescence and herpes-type virus particles in the P3HR-1 Burkitt lymphoma cell line. J Virol, 1, 1045-51.
118. Holley-Guthrie, E. A., E. B. Quinlivan, E. C. Mar & S. Kenney (1990) The Epstein-Barr virus (EBV) BMRF1 promoter for early antigen (EA-D) is regulated by the EBV transactivators, BRLF1 and BZLF1, in a cell-specific manner. J Virol, 64, 3753-9.
119. Liu, C., N. D. Sista & J. S. Pagano (1996) Activation of the Epstein-Barr virus DNA polymerase promoter by the BRLF1 immediate-early protein is mediated through USF and E2F. J Virol, 70, 2545-55.
120. Nemerow, G. R., C. Mold, V. K. Schwend, V. Tollefson & N. R. Cooper (1987) Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J Virol, 61, 1416-20.
121. Ragoczy, T. & G. Miller (1999) Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. J Virol, 73, 9858-66.
122. Swenson, J. J., A. E. Mauser, W. K. Kaufmann & S. C. Kenney (1999) The Epstein-Barr virus protein BRLF1 activates S phase entry through E2F1 induction. J Virol, 73, 6540-50.
123. Urier, G., M. Buisson, P. Chambard & A. Sergeant (1989) The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J, 8, 1447-53.
124. Wang, F., C. Gregory, C. Sample, M. Rowe, D. Liebowitz, R. Murray, A. Rickinson & E. Kieff (1990) Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol, 64, 2309-18.
125. Zalani, S., E. A. Holley-Guthrie, D. E. Gutsch & S. C. Kenney (1992) The Epstein-Barr virus immediate-early promoter BRLF1 can be activated by the cellular Sp1 transcription factor. J Virol, 66, 7282-92.