An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation

PLoS Pathogens

Volumn 13, Issue 7, 2017, Pages

  Pei, Yonggang ^a   Banerjee, Shuvomoy ^a,b   Jha, Hem Chandra ^a,c   Sun, Zhiguo ^a   Robertson, Erle S ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b AMITY UNIVERSITY   (India)

^c Centre for Biosciences and Biomedical Engineeringn Institute of Technology Indore   (India)

Author keywords

[No Author keywords available]

Indexed keywords

EPSTEIN BARR VIRUS ANTIGEN; EPSTEIN BARR VIRUS LATENT ANTIGEN 3C; INTERFERON REGULATORY FACTOR 4; MESSENGER RNA; PROTEIN BCL 2; PROTEIN BCL 6; UNCLASSIFIED DRUG; EBNA-3C, EPSTEIN-BARR VIRUS; INTERFERON REGULATORY FACTOR; INTERFERON REGULATORY FACTOR-4; PROTEIN BINDING;

ANCHORAGE INDEPENDENT GROWTH; ANTIGEN BINDING; ANTIGEN EXPRESSION; ARTICLE; B LYMPHOCYTE; CELL CYCLE CHECKPOINT; CELL CYCLE G1 PHASE; CELL CYCLE S PHASE; CELL PROLIFERATION; CELL TRANSFORMATION; CHROMATIN IMMUNOPRECIPITATION; COLONY FORMATION; CONFOCAL MICROSCOPY; DOWN REGULATION; FLOW CYTOMETRY; GENE EXPRESSION; GERMINAL CENTER; HUMAN; HUMAN CELL; IMAGE ANALYSIS; IMMUNOFLUORESCENCE TEST; LUCIFERASE ASSAY; PERIPHERAL BLOOD MONONUCLEAR CELL; POLYACRYLAMIDE GEL ELECTROPHORESIS; PROMOTER REGION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN INTERACTION; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; RNA ISOLATION; UPREGULATION; WESTERN BLOTTING; EPSTEIN BARR VIRUS; EPSTEIN BARR VIRUS INFECTION; GENE EXPRESSION REGULATION; GENETICS; HOST PATHOGEN INTERACTION; METABOLISM; PATHOPHYSIOLOGY; VIROLOGY;

CELL PROLIFERATION; EPSTEIN-BARR VIRUS INFECTIONS; EPSTEIN-BARR VIRUS NUCLEAR ANTIGENS; GENE EXPRESSION REGULATION; HERPESVIRUS 4, HUMAN; HOST-PATHOGEN INTERACTIONS; HUMANS; INTERFERON REGULATORY FACTORS; PROMOTER REGIONS, GENETIC; PROTEIN BINDING; PROTEOLYSIS; PROTO-ONCOGENE PROTEINS C-BCL-6;

EID: 85026884717     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1006500     Document Type: Article

References (81)

1. Kurosaki T, (2010) B-lymphocyte biology. Immunol Rev237: 5–9. doi: 10.1111/j.1600-065X.2010.00946.x 20727025
2. Basso K, Dalla-Favera R, (2015) Germinal centres and B cell lymphomagenesis. Nat Rev Immunol15: 172–184. doi: 10.1038/nri3814 25712152
3. Kuppers R, Klein U, Hansmann ML, Rajewsky K, (1999) Cellular origin of human B-cell lymphomas. N Engl J Med341: 1520–1529. doi: 10.1056/NEJM199911113412007 10559454
4. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, et al. (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature403: 503–511. doi: 10.1038/35000501 10676951
5. Ok CY, Papathomas TG, Medeiros LJ, Young KH, (2013) EBV-positive diffuse large B-cell lymphoma of the elderly. Blood122: 328–340. doi: 10.1182/blood-2013-03-489708 23649469
6. Kuze T, Nakamura N, Hashimoto Y, Sasaki Y, Abe M, (2000) The characteristics of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma: comparison between EBV(+) and EBV(-) cases in Japanese population. Jpn J Cancer Res91: 1233–1240. 11123421
7. Baron BW, Billstrand C, Madronero L, McKeithan TW, (1993) HindIII polymorphism in the BCL6 gene. Hum Mol Genet2: 1513. 7902168
8. Ye BH, Rao PH, Chaganti RS, Dalla-Favera R, (1993) Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res53: 2732–2735. 8504412
9. Chang CC, Ye BH, Chaganti RS, Dalla-Favera R, (1996) BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci U S A93: 6947–6952. 8692924
10. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM, (1997) Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science276: 589–592. 9110977
11. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, et al. (1997) The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet16: 161–170. doi: 10.1038/ng0697-161 9171827
12. Migliazza A, Martinotti S, Chen W, Fusco C, Ye BH, et al. (1995) Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci U S A92: 12520–12524. 8618933
13. Gaidano G, Carbone A, Pastore C, Capello D, Migliazza A, et al. (1997) Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Blood89: 3755–3762. 9160681
14. Ye BH, (2000) BCL-6 in the pathogenesis of non-Hodgkin's lymphoma. Cancer Invest18: 356–365. 10808372
15. Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RS, et al. (2003) Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood101: 2914–2923. doi: 10.1182/blood-2002-11-3387 12515714
16. Perez-Rosado A, Artiga M, Vargiu P, Sanchez-Aguilera A, Alvarez-Barrientos A, et al. (2008) BCL6 represses NFkappaB activity in diffuse large B-cell lymphomas. J Pathol214: 498–507. doi: 10.1002/path.2279 18189332
17. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, et al. (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity13: 199–212. 10981963
18. Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, et al. (2004) Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol173: 1158–1165. 15240705
19. Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H, et al. (2016) Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J Clin Invest.
20. Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, et al. (2010) A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell17: 400–411. doi: 10.1016/j.ccr.2009.12.050 20385364
21. Cerchietti LC, Yang SN, Shaknovich R, Hatzi K, Polo JM, et al. (2009) A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo. Blood113: 3397–3405. doi: 10.1182/blood-2008-07-168773 18927431
22. Jha H, Pei Y, Robertson E, (2016) Epstein Barr virus: Diseases linked to Infection and Transformation. Frontiers in Microbiology7.
23. Young LS, Yap LF, Murray PG, (2016) Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer.
24. Mesri EA, Feitelson MA, Munger K, (2014) Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe15: 266–282. doi: 10.1016/j.chom.2014.02.011 24629334
25. Saha A, Robertson ES, (2011) Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes. Clin Cancer Res17: 3056–3063. doi: 10.1158/1078-0432.CCR-10-2578 21372216
26. Cohen JI, Wang F, Mannick J, Kieff E, (1989) Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A86: 9558–9562. 2556717
27. Maruo S, Zhao B, Johannsen E, Kieff E, Zou J, et al. (2011) Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A108: 1919–1924. doi: 10.1073/pnas.1019599108 21245331
28. Humme S, Reisbach G, Feederle R, Delecluse HJ, Bousset K, et al. (2003) The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci U S A100: 10989–10994. doi: 10.1073/pnas.1832776100 12947043
29. West MJ, (2006) Structure and function of the Epstein-Barr virus transcription factor, EBNA 3C. Curr Protein Pept Sci7: 123–136. 16611138
30. Subramanian C, Knight JS, Robertson ES, (2002) The Epstein Barr nuclear antigen EBNA3C regulates transcription, cell transformation and cell migration. Front Biosci7: d704–716. 11861219
31. Bajaj BG, Murakami M, Cai Q, Verma SC, Lan K, et al. (2008) Epstein-Barr virus nuclear antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein. J Virol82: 4082–4090. doi: 10.1128/JVI.02500-07 18256156
32. Banerjee S, Lu J, Cai Q, Saha A, Jha HC, et al. (2013) The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8. PLoS Pathog9: e1003314. doi: 10.1371/journal.ppat.1003314 23658517
33. Touitou R, Hickabottom M, Parker G, Crook T, Allday MJ, (2001) Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus nuclear antigen EBNA3C. J Virol75: 7749–7755. doi: 10.1128/JVI.75.16.7749-7755.2001 11462050
34. Yi F, Saha A, Murakami M, Kumar P, Knight JS, et al. (2009) Epstein-Barr virus nuclear antigen 3C targets p53 and modulates its transcriptional and apoptotic activities. Virology388: 236–247. doi: 10.1016/j.virol.2009.03.027 19394062
35. Saha A, Lu J, Morizur L, Upadhyay SK, Aj MP, et al. (2012) E2F1 mediated apoptosis induced by the DNA damage response is blocked by EBV nuclear antigen 3C in lymphoblastoid cells. PLoS Pathog8: e1002573. doi: 10.1371/journal.ppat.1002573 22438805
36. Pei Y, Banerjee S, Sun Z, Jha HC, Saha A, et al. (2016) EBV Nuclear Antigen 3C Mediates Regulation of E2F6 to Inhibit E2F1 Transcription and Promote Cell Proliferation. PLoS Pathog12: e1005844. doi: 10.1371/journal.ppat.1005844 27548379
37. Carbone A, Gaidano G, Gloghini A, Pastore C, Saglio G, et al. (1997) BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression. Am J Pathol150: 155–165. 9006332
38. Martin-Perez D, Vargiu P, Montes-Moreno S, Leon EA, Rodriguez-Pinilla SM, et al. (2012) Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma. Leukemia26: 180–183. doi: 10.1038/leu.2011.189 21788950
39. Boccellato F, Anastasiadou E, Rosato P, Kempkes B, Frati L, et al. (2007) EBNA2 interferes with the germinal center phenotype by downregulating BCL6 and TCL1 in non-Hodgkin's lymphoma cells. J Virol81: 2274–2282. doi: 10.1128/JVI.01822-06 17151114
40. Saha A, Halder S, Upadhyay SK, Lu J, Kumar P, et al. (2011) Epstein-Barr virus nuclear antigen 3C facilitates G1-S transition by stabilizing and enhancing the function of cyclin D1. PLoS Pathog7: e1001275. doi: 10.1371/journal.ppat.1001275 21347341
41. Phan RT, Saito M, Kitagawa Y, Means AR, Dalla-Favera R, (2007) Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells. Nat Immunol8: 1132–1139. doi: 10.1038/ni1508 17828269
42. Niu H, Ye BH, Dalla-Favera R, (1998) Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev12: 1953–1961. 9649500
43. Knight JS, Sharma N, Robertson ES, (2005) Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase. Proc Natl Acad Sci U S A102: 18562–18566. doi: 10.1073/pnas.0503886102 16352731
44. Saha A, Murakami M, Kumar P, Bajaj B, Sims K, et al. (2009) Epstein-Barr virus nuclear antigen 3C augments Mdm2-mediated p53 ubiquitination and degradation by deubiquitinating Mdm2. J Virol83: 4652–4669. doi: 10.1128/JVI.02408-08 19244339
45. Zhang TT, Liu D, Calabro S, Eisenbarth SC, Cattoretti G, et al. (2014) Dynamic expression of BCL6 in murine conventional dendritic cells during in vivo development and activation. PLoS One9: e101208. doi: 10.1371/journal.pone.0101208 24979752
46. Basso K, Dalla-Favera R, (2012) Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev247: 172–183. doi: 10.1111/j.1600-065X.2012.01112.x 22500840
47. Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, et al. (2007) A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell12: 280–292. doi: 10.1016/j.ccr.2007.08.011 17785208
48. Robertson ES, Grossman S, Johannsen E, Miller C, Lin J, et al. (1995) Epstein-Barr virus nuclear protein 3C modulates transcription through interaction with the sequence-specific DNA-binding protein J kappa. J Virol69: 3108–3116. 7707539
49. Saha A, Bamidele A, Murakami M, Robertson ES, (2011) EBNA3C attenuates the function of p53 through interaction with inhibitor of growth family proteins 4 and 5. J Virol85: 2079–2088. doi: 10.1128/JVI.02279-10 21177815
50. Margalit O, Amram H, Amariglio N, Simon AJ, Shaklai S, et al. (2006) BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma. Blood107: 1599–1607. doi: 10.1182/blood-2005-04-1629 16249378
51. Ma SD, Xu X, Plowshay J, Ranheim EA, Burlingham WJ, et al. (2015) LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis. J Clin Invest125: 304–315. doi: 10.1172/JCI76357 25485679
52. Saito M, Novak U, Piovan E, Basso K, Sumazin P, et al. (2009) BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A106: 11294–11299. doi: 10.1073/pnas.0903854106 19549844
53. Czabotar PE, Lessene G, Strasser A, Adams JM, (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol15: 49–63. doi: 10.1038/nrm3722 24355989
54. Bereshchenko OR, Gu W, Dalla-Favera R, (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat Genet32: 606–613. doi: 10.1038/ng1018 12402037
55. Shvarts A, Brummelkamp TR, Scheeren F, Koh E, Daley GQ, et al. (2002) A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. Genes Dev16: 681–686. doi: 10.1101/gad.929302 11914273
56. Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, et al. (1993) Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science262: 747–750. 8235596
57. Dhordain P, Lin RJ, Quief S, Lantoine D, Kerckaert JP, et al. (1998) The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res26: 4645–4651. 9753732
58. Dhordain P, Albagli O, Lin RJ, Ansieau S, Quief S, et al. (1997) Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc Natl Acad Sci U S A94: 10762–10767. 9380707
59. Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, et al. (2004) MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell119: 75–86. doi: 10.1016/j.cell.2004.09.014 15454082
60. Huynh KD, Bardwell VJ, (1998) The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene17: 2473–2484. doi: 10.1038/sj.onc.1202197 9824158
61. Kalchschmidt JS, Bashford-Rogers R, Paschos K, Gillman AC, Styles CT, et al. (2016) Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells. J Exp Med213: 921–928. doi: 10.1084/jem.20160120 27217538
62. White RE, Groves IJ, Turro E, Yee J, Kremmer E, et al. (2010) Extensive co-operation between the Epstein-Barr virus EBNA3 proteins in the manipulation of host gene expression and epigenetic chromatin modification. PLoS One5: e13979. doi: 10.1371/journal.pone.0013979 21085583
63. Duan S, Cermak L, Pagan JK, Rossi M, Martinengo C, et al. (2012) FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature481: 90–93. doi: 10.1038/nature10688 22113614
64. Niu H, Cattoretti G, Dalla-Favera R, (2003) BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells. J Exp Med198: 211–221. doi: 10.1084/jem.20021395 12860928
65. Basso K, Dalla-Favera R, (2010) BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol105: 193–210. doi: 10.1016/S0065-2776(10)05007-8 20510734
66. Ohno H, (2006) Pathogenetic and clinical implications of non-immunoglobulin; BCL6 translocations in B-cell non-Hodgkin's lymphoma. J Clin Exp Hematop46: 43–53. 17142954
67. Ye BH, Chaganti S, Chang CC, Niu H, Corradini P, et al. (1995) Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J14: 6209–6217. 8557040
68. Lee CH, Melchers M, Wang H, Torrey TA, Slota R, et al. (2006) Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J Exp Med203: 63–72. doi: 10.1084/jem.20051450 16380510
69. Basso K, Saito M, Sumazin P, Margolin AA, Wang K, et al. (2010) Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood115: 975–984. doi: 10.1182/blood-2009-06-227017 19965633
70. Ci W, Polo JM, Cerchietti L, Shaknovich R, Wang L, et al. (2009) The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood113: 5536–5548. doi: 10.1182/blood-2008-12-193037 19307668
71. Kinugasa Y, Hieda M, Hori M, Higashiyama S, (2007) The carboxyl-terminal fragment of pro-HB-EGF reverses Bcl6-mediated gene repression. J Biol Chem282: 14797–14806. doi: 10.1074/jbc.M611036200 17392284
72. Kusam S, Vasanwala FH, Dent AL, (2004) Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function. Oncogene23: 839–844. doi: 10.1038/sj.onc.1207065 14737119
73. Nahar R, Ramezani-Rad P, Mossner M, Duy C, Cerchietti L, et al. (2011) Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC. Blood118: 4174–4178. doi: 10.1182/blood-2011-01-331181 21856866
74. Wei F, Zaprazna K, Wang J, Atchison ML, (2009) PU.1 can recruit BCL6 to DNA to repress gene expression in germinal center B cells. Mol Cell Biol29: 4612–4622. doi: 10.1128/MCB.00234-09 19564417
75. Chevallier N, Corcoran CM, Lennon C, Hyjek E, Chadburn A, et al. (2004) ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. Blood103: 1454–1463. doi: 10.1182/blood-2003-06-2081 14551142
76. Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P, et al. (2008) AID is required for germinal center-derived lymphomagenesis. Nat Genet40: 108–112. doi: 10.1038/ng.2007.35 18066064
77. Liu X, Lu H, Chen T, Nallaparaju KC, Yan X, et al. (2016) Genome-wide Analysis Identifies Bcl6-Controlled Regulatory Networks during T Follicular Helper Cell Differentiation. Cell Rep14: 1735–1747. doi: 10.1016/j.celrep.2016.01.038 26876184
78. Halder S, Murakami M, Verma SC, Kumar P, Yi F, et al. (2009) Early events associated with infection of Epstein-Barr virus infection of primary B-cells. PLoS One4: e7214. doi: 10.1371/journal.pone.0007214 19784370
79. (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood89: 3909–3918. 9166827
80. Subramanian C, Cotter MA, 2ndRobertson ES, (2001) Epstein-Barr virus nuclear protein EBNA-3C interacts with the human metastatic suppressor Nm23-H1: a molecular link to cancer metastasis. Nat Med7: 350–355. doi: 10.1038/85499 11231635
81. Pei Y, Fu W, Yang E, Shen A, Chen YC, et al. (2012) A Hsp40 chaperone protein interacts with and modulates the cellular distribution of the primase protein of human cytomegalovirus. PLoS Pathog8: e1002968. doi: 10.1371/journal.ppat.1002968 23133382