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研究生:王錦堂
研究生(外文):Jiin-Tarng Wang
論文名稱:EB病毒BGLF4蛋白激酶特性及其抑制干擾素調節因子3訊息傳遞功能之研究
論文名稱(外文):Characterization of Epstein-Barr virus BGLF4 kinase and its effect on repressing interferon regulatory factor 3signaling pathway
指導教授:陳美如陳美如引用關係
指導教授(外文):Mei-Ru Chen
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:78
中文關鍵詞:蛋白激酶干擾素調節因子3
外文關鍵詞:BGLF4 kinaseinterferon regulatory factor 3
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EB病毒感染全世界超過百分之九十的人口,而且和一些惡性腫瘤例如淋巴癌、鼻咽癌、胃癌以及移植後淋巴癌有高度相關性。為了更加了解這些疾病和病毒致病因子之間的關係,在本研究中,探討EB病毒所合成出以辨識脯胺酸絲胺酸/酥胺酸(Ser/Thr Pro)的BGLF4蛋白激酶,在病毒致病因子和宿主細胞之間的交互作用及其生物意義。為了探討BGLF4的可能功能,首先利用BGLF4的專一性單株抗體,偵測BGLF4在EB病毒複製的細胞中主要位在核內,同時也被包裹在病毒顆粒中。經由酵母雙雜交系統的篩選,發現干擾素調控因子3 (IRF3)的剪接變異體可以和BGLF4蛋白交互作用,並經短暫性轉染共同沉澱法和試管內GST-融合蛋白沉澱方法確定其交互作用。在利用報導質體分析中,BGLF4有效抑制poly(I:C)所刺激的干擾素β啟動子和IRF3反應區域的活性。而且BGLF4有效的抑制內生性干擾素βmRNA的表現以及STAT1 (Signal Transducers and Activators of Transcription protein 1)在第701個胺基酸酪氨酸的位置的磷酸化。進一步探討可能的機轉,BGLF4不影響poly(I:C)所引起IRF3形成雙聚體,轉移至核內,或是與CBP (cAMP Response Element Binding Protein)結合的能力。利用染色質免疫沉澱分析法,發現BGLF4會減少被活化的IRF3結合在帶有IRF3反應區域的之干擾素β啟動子上。BGLF4可以在試管內磷酸化GST-IRF3。利用點突變的分析發現絲胺酸339-脯胺酸340的磷酸化所引發Pin1的調控方式並不涉及BGLF4對IRF3的抑制作用;而是位於IRF3 DNA結合區域和干擾素調控因子結合區域中間的3個SP序列,包括Ser123、Ser173及Thr180的磷酸化可以加成性地反應BGLF4抑制IRF3的轉活化功能。同時發現在被活化進入溶裂期的EB病毒陽性NA細胞中,IRF3 也被活化。若送入siRNA抑制BGLF4的表現量,則帶有IRF3反應區域的報導質體活性會被提高。本研究的結果發現疱疹病毒的蛋白激酶可以透過一種新的機制抑制細胞的干擾素活化,以利病毒複製。
Epstein-Barr virus (EBV) infects more than 90% worldwide population, and is highly associated with many malignancies such as lymphoma, nasopharyngeal carcinoma (NPC), gastric carcinoma, and post-transplantation lymphoma diseases. In this study, EBV encoded proline-directed ser/thr protein kinase BGLF4 was studied for the interplay between virus virulent factors and the host factors and the biological significance of the interaction. To search for the possible functions of BGLF4, specific monoclonal antibodies (MoAbs) were generated to demonstrate that BGLF4 mainly localized in the nucleus of the EBV positive epithelial cells, and it is a virion-associated protein kinase. Moreover, through a yeast two-hybrid screening approach, a splicing variant of interferon regulatory factor 3 (IRF3) was found to interact with BGLF4 protein. This interaction was further defined by co-immunoprecipitation in transfected cells and GST pull-down in vitro. Using reporter assays, BGLF4 effectively suppressed the poly(I:C)-stimulated IFNβ promoter and IRF3 responsive element activities. Moreover, BGLF4 repressed poly(I:C)-stimulated expression of endogenous IFNβ mRNA and phosphorylation of STAT1 at Tyr701. In searching for a possible mechanism, BGLF4 did not affect dimerization, nuclear translocation, or CBP recruitment of IRF3 upon poly(I:C)treatment. Notably, BGLF4 reduced the amount of active IRF3 recruited to the IRF3 responsive element (IRE) containing the IFNβ promoter region in a ChIP assay. BGLF4 phosphorylated GST-IRF3 in vitro, but Ser339-Pro340 phosphorylationdependent, Pin1-mediated down regulation is not responsible for the repression. Most importantly, three proline-dependent phosphorylation sites at Ser123, Ser173 and Thr180, which cluster in a region between the DNA binding and IRF association domains of IRF3, contributed additively to BGLF4 mediated repression of IRF3(5D) transactivation activity. IRF3 signaling was activated in reactivated EBV positive NA cells, and knockdown of BGLF4 further stimulated IRF3 responsive reporter activity. The data presented here thus provide a novel mechanism by which herpes viral protein kinases suppress host innate immune responses and facilitate virus replication.
中文摘要………………………………………………………………… I
Abstract……………………………………………………………… II
Contents……………………………………………………………… IV
Chapter 1: Introduction……………………………………………………… 1
1.1 Epstein-Barr virus………………………………………………1
1.1.1 The viral structure and genome of EBV………………… 1
1.1.2 The life cycle of EBV……………………………………… 1
1.1.3 EBV associated diseases…………………………………… 2
1.2 Innate immunity………………………………………………… 3
1.2.1 Interplay between virus and innate immunity………… 3
1.2.2 Herpesvirus and innate immune responses………………7
1.3 BGLF4 protein kinase………………………………………… 7
1.3.1 Regulatory function of BGLF4……………………………… 8
1.4 Interferon regulatory factor 3……………………………… 9
1.5 Aims of this study…………………………………………… 10
Chapter 2 Results………………………………………………………… 11
2.1 Generation of BGLF4 MoAbs…………………………………… 11
2.2 Characterization of the expression of BGLF4 protein kinase in EBV positive cells……………………… 12
2.2.1 Detection of BGLF4 protein in EBV replicating epithelial cells……………………………12
2.2.2 Identification of BGLF4 as the virion-associated protein kinase………………………… 13
2.3 BGLF4 suppresses interferon regulatory factor 3 transactivation activity…………… 14
2.3.1 BGLF4 interacts with a splicing variant and authentic form of IRF3……………………… 15
2.3.2 BGLF4 suppresses IRF3-dependent transcriptional activation…………………… 17
2.3.3 BGLF4 suppresses endogenous poly(I:C)-triggered signaling pathway ……………18
2.3.4 BGLF4 does not suppress poly(I:C)-triggered IRF3 dimerization, translocation, or CBP recruitment…………………………………. 19
2.3.5 BGLF4 suppresses poly(I:C)-triggered IRF3 binding to PRDIII-I of IFNβ promoter………………………………...... 20
2.3.6 BGLF4 phosphorylates IRF3 in vitro, but does not adapt a Pin1-mediated IRF3 degradation mechanism to block IRF3 signaling… 20
2.3.7 Ser123, Ser173 and Thr180 of IRF3 contribute additively to BGLF4 mediated suppression of IRF3(5D)……………………………... 21
2.3.8 Knockdown of BGLF4 enhances IRF3 responsive reporter activity in EBV-reactivated cells………………………………22
Chapter 3: Discussion…………………………………………… 23
3.1 Characterization of BGLF4 in EBV positive cells………23
3.2 BGLF4 suppresses IRF3 signaling pathway………………… 24
3.3 Closing remarks………………………………………………… 27
Chapter 4: Materials & Methods………………………………… 29
4.1 Plasmid construction………………………………………… 29
4.2 Cell culture, transfection, and induction of viral lytic cycle………………………………31
4.3 Purification of bacterially expressed recombinant BGLF4……………… 31
4.4 Generation of BGLF4 specific MoAbs……………………… 32
4.5 Immunoprecipitation assay…………………………………… 32
4.6 Indirect immunofluorescence………………………………… 33
4.7 Purification of EBV viral particles………………………33
4.8 Virion DNA extraction and polymerase chain reaction………………… 34
4.9 Electron microscopy………………………………………… 34
4.10 Yeast two-hybrid screening………………………………… 34
4.11 dsRNA stimulation…………………………………………… 35
4.12 Co-immunoprecipitation……………………………………… 35
4.13 Expression and purification of GST fusion proteins…………………… 35
4.14 In vitro transcription/translation………………………36
4.15 GST pull-down assays…………………………………………36
4.16 Reporter assays………………………………………………………….… 36
4.17 RNA purification and quantitative real-time RT-PCR………………….… 37
4.18 Analysis of IRF-3 dimerization by native PAGE…………………………. 37
4.19 Chromatin immunoprecipitation (ChIP) assay……………………………. 38
4.20 Immunoprecipitation kinase assay…………………………39
4.21 Reporter assay of IRF3 responsive activity in EBV positive NA cells and design of siBGLF4………………………………………………………... 40

Table
Table 1 Summary of characterization of BGLF4 MoAbs……………………. 41
Table 2 Oligonucleotide primers and DNA templates used to generate site-directed mutants of IRF3(5D)………………………………… 42
Figures
Fig. 1 Characterization of BGLF4 MoAbs …………………………………… 43
Fig. 2 Immunogenic epitopes of BGLF4 recognized by different MoAbs were analyzed by immunoblotting…………………………………………… 44
Fig. 3 Expression of BGLF4 protein in EBV-positive NA cells……………… 45
Fig. 4 Detection of BGLF4 protein in EBV viral particles…………………… 46
Fig. 5 BGLF4 interacts with a splicing variant and authentic form of IRF3………………47
Fig. 6 BGLF4 interacts IRF3 in transiently transfected HeLa cells…………………………………… 48
Fig. 7 BGLF4 does not interact with GFP in transiently transfected HeLa cells……………… 49
Fig. 8 BGLF4 interacts with IRF3 in vitro………………… 50
Fig. 9 Schematic diagram of DNA sequence and transcription factor binding sites VII of the IFNβ promoter (Wathelet et al., 1998)…………………… 51
Fig. 10 BGLF4 suppresses IRF3 transactivation activity in transient reporter assay 52
Fig. 11 BGLF4 suppresses endogenous poly(I:C)-triggered signaling pathway... 53
Fig. 12 BGLF4 does not suppress poly(I:C)-triggered IRF3 dimerization……… 54
Fig. 13 BGLF4 does not suppress poly(I:C)-triggered IRF3 translocation……… 55
Fig. 14 BGLF4 does not suppress poly(I:C)-triggered IRF3 to recruit CBP………56
Fig. 15 BGLF4 suppresses poly(I:C)-triggered IRF3 binding to PRDIII-I of IFNβ promoter……………………………… 57
Fig. 16 BGLF4 phosphorylates IRF3 in vitro………………… 58
Fig. 17 BGLF4 does not adapt a Pin1-mediated mechanism to block IRF3 activation…………………………………………… 59
Fig. 18 Summary of currently identified phosphorylation sites on IRF3 and IRF3(5D) based mutants used in this study……………………………… 60
Fig. 19 Ser123, Ser173 and Thr180 of IRF3 contribute additively to BGLF4 mediated suppression of IRF3(5D) in transient reporter assay………….. 61
Fig. 20 BGLF4 interacts with IRF3 in EBV reactivated EBV positive epithelial cells…………………………………. 62
Fig. 21 Knockdown of BGLF4 enhances IRF3 responsive reporter activity in EBV reactivated NPC cells……………………………………………………... 63
Fig. 22 The hypothetic model of BGLF4 function in repressing IRF3 transactivation in EBV positive cells…………………………………………………….. 64
Fig. 23 Strategies of BGLF4 to counteract cellular limitation and facilitate viral
replication…………………………………………………………65
References…………………………………………………………… 66
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