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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳美如(Mei-Ru Chen) | |
dc.contributor.author | Yi-Jie Juang | en |
dc.contributor.author | 莊詒捷 | zh_TW |
dc.date.accessioned | 2021-05-19T17:57:26Z | - |
dc.date.available | 2021-08-26 | |
dc.date.available | 2021-05-19T17:57:26Z | - |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7889 | - |
dc.description.abstract | 當EB 病毒進入宿主細胞後,其線型DNA 會進到細胞核內成為環型結構,當病毒於細胞內呈潛伏期時,其DNA 會隨著細胞週期進行複製。當病毒進入溶裂期複製,病毒DNA 在核內完成複製與殼體組裝後成為核殼體,會藉由出核複合體BFRF1/BFLF2 促進核殼體由細胞核穿越核膜並釋出至細胞質。實驗室先前證明BFRF1 會透過Alix 吸引 ESCRT (endosomal sorting complex required for transport) 膜剪切模組幫助BFRF1 產生核模衍生液泡 (nuclear envelope-derived vesicle) 以加速核殼體出核。由於ESCRT 系統是由三十多個成員串連而執行功能,已知參與細胞內膜的剪接運輸及多種病毒的成熟過程。對於ESCRT 如何參與核膜結構的改變仍只有少數研究報導,因此在本論文中首先探討BFRF1 如何利用其不同功能區域吸引Alix 並將核膜塑形產生核膜衍生液泡。同時利用不同ESCRT 成員的shRNA 使其表現量下降,以探討那些ESCRT 膜剪切蛋白成員會參與在EB 病毒核殼體出核的過程。為了之後得
到大量的BFRF1 蛋白質以建構抗體,本論文也嘗試建立大腸菌產生的重組BFRF1 蛋白質表現系統。本論文之結果發現(I)在共免疫沉澱試驗中發現BFRF1 會分別利用LD1 (8-65 a.a) 與ESR (180-313 a.a) 和Alix 的Bro (1-358 a.a)及PRR (703–868 a.a) 功能區域結合。當 BFRF1 這兩個區域的刪除或是點突變會影響到細胞內Alix 的分布及 BFRF1 產生核膜衍生液泡的能力。(II)同時也利用含有EB 病毒的鼻咽癌上皮細胞NA 觀察,以shRNA 病毒使ESCRT 表現量下降時,會影響釋出細胞的病毒數量。(III)利用大腸桿菌表現大量重組BFRF1 蛋白,可用於生產高專一性的抗體,以探討BFRF1 在 EB 病毒核殼體出核過程的路徑與機制。這些發現將有助於了解BFRF1 在調控核膜塑形上的分子機制。 | zh_TW |
dc.description.abstract | Upon its entrance into the cell, the linear EBV genome is injected into the nucleusand becomes circular episomes, which can be maintained in these cells during latent infection. When virus is induced into lytic replication, the replicated viral genomes are packaged into procapsids to form nucleocapsids in the nucleus before translocated
into the cytoplasm for subsequent maturation process. The nuclear egress complex (NEC) composed of BFRF1 and BFLF2 can facilitate the budding of nucleocapsids across the nuclear envelope (NE). Previously, our laboratory emonstrated that BFRF1 interacts with Alix to recruit ESCRT (endosomal sorting complex required for transport) machinery to induce nuclear envelope-derived vesicles for promoting nuclear egress. ESCRT machinery is composed of at least 30 proteins to mediate membrane scission and cytoplasmic budding of various virus. How the ESCRT system is involved in modulating nuclear envelope structure is just immerging. Therefore, in the first part of this study, we intend to define how the viral membrane protein BFRF1 recruits Alix and the functional domains required for nuclear envelope-derived vesicle formation. Secondly, a shRNA approach is used to knockdown individual ESCRT components to examine the participation of different ESCRT components in EBV nuclear egress or mature virion secretion. Bacterially expressed recombinant BFRF1 protein expression system was used to obtain purified BFRF1 for generating antibody. Three different aspects of BFRF1 is achieved in this study. (I) Co-immunoprecipitation results showed that LD1 (8-65 a.a ) and ESR (180- 313 a.a) domains of BFRF1 interacted with Alix Bro (1-358 a.a) and PRR (703-868 a.a), respectively. Site-directed mutagenesis of LD1 or ESR in BFRF1 reduced BFRF1 induced vesicle formation and affected cellular Alix subcellular distribution. (II) shRNA targeting various ESCRT components were used in EBV positive epithelial cells NA, the preliminary data indicate that knockdown of ESCRT components does affect virion release but not viral DNA replication. (III)A bacterially recombinant BFRF1 protein was expressed and purified for generating highly specific antibody to study the intracellular trafficking of BFRF1 during EBV nuclear egress process. Overall, this study will help to reveal the molecular mechanisms of BFRF1-mediated budding and scission of EBV nuclear egress vesicles. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:57:26Z (GMT). No. of bitstreams: 1 ntu-105-R03445108-1.pdf: 2290067 bytes, checksum: a88f774158b292823f0843d3769c727c (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 1. 序論 1
1.1 EB病毒(Epstein-Barr virus) 1 1.1.1 EB病毒與疾病 1 1.1.2 EB病毒基因體與結構 1 1.1.3 EB病毒生活史 2 1.2 疱疹病毒顆粒出核過程(nuclear egress) 5 1.2.1 核膜結構 5 1.2.2 疱疹病毒利用蛋白質激酶促使 nuclear lamina結構鬆散,促使核殼體出核 6 1.2.3 初次套膜化(primary envelopment) 6 1.2.4 去套膜化 (de-envelopment) 7 1.2.5 二次套膜化 (secondary envelopment or re-envelopment) 7 1.3 BFRF1 及其同源蛋白質 8 1.3.1 BFRF1 在α型疱疹病毒的同源蛋白質 (UL34) 8 1.3.2 BFRF1 蛋白質在EB病毒中的發現與功能 8 1.4 BFRF1 衍生液泡結構可能與 ESCRT 膜剪切機制相關 10 1.4.1 ESCRT (Endosomal Sorting Complex Required for Transport) 10 1.4.2 BFRF1 和 Alix 的結合並與核膜產生衍生液泡 11 1.5 研究目的 11 2. 實驗材料與方法 13 2.1 建構質體 13 2.1.1 本論文建構之質體 13 2.1.2 其他質體 14 2.3 引子序列 16 2.4 細胞培養 16 2.5 細胞轉染 16 2.6 正二十丙烷硫酸鈉-聚丙烯胺凝膠電泳 (sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 及西方墨點法(Western Blot) 17 2.7 共同免疫沉澱(co-immunoprecipitation) 17 2.8 間接免疫螢光染色(indirect immunofluorescence assay) 18 2.9 表現及純化BFRF1蛋白 19 2.10 慢病毒製備 (Lentivirus packaging) 21 2.11 慢病毒感染 (Lentivirus infection) 21 2.12 細胞內EBV病毒核酸萃取 21 2.13 細胞外EBV病毒核酸萃取 22 2.14 即時定量聚合酶連鎖反應 (Quantitative polymerase chain reaction) 23 3. 實驗結果 24 3.1 BFRF1 的 ESR 功能區正電胺基酸,對於 BFRF1 和 Alix PRR 功能區的結合是重要的 24 3.2 HA-BFRF1 mutants 使衍生液泡減少並且改變內生性 Alix 於細胞內的分布位置 25 3.3 HA-BFRF1 mutants 減弱核膜塑形能力使核膜衍生液泡減少 25 3.4 以免疫沉澱法偵測 BFRF1 mutants 與 Alix 蛋白結合能力無明顯差異 26 3.5 pLenti4-GFP-BFRF1 短暫的轉染與篩選為誘導穩定細胞株後的表現形態不同 27 3.6 Knockdown Chmp4B 和 Vps4A 促進 EBV 病毒釋出 28 3.7 Knockdown ESCRT-III (Chmp4A/Chmp4B/Chmp4C/Chmp6/Chmp7) 對促進 EBV 病毒的釋出 28 3.8 Knockdown ESCRT-III (Vps4A/Chmp1B/Chmp2B/Chmp3) 對於EBV 病毒複製與釋出的影響 29 3.9 建立細菌表現重組蛋白His-BFRF1及以變性環境的純化系統 30 4. 討論 32 4.1 HA-BFRF1 mutants 使衍生液泡減少的可能原因 32 4.2 透過其他蛋白-蛋白結合試驗偵測 BFRF1 mutants 與 Alix 蛋白結合能力 32 4.3 pLenti4-GFP-BFRF1 轉染初期與篩選為誘導穩定細胞株後的表現形態不同的原因 33 4.4 NA細胞以Rta質體轉染誘導進入融裂期,因誘導時間不同而使extracellular EBV copy number有所差異 33 4.5 ESCRT-III 蛋白對於調控EB病毒殼體釋出的意義 33 4.6 總結 34 Figure 36 圖一、當BFRF1的 ESR 功能區正電胺基酸突變時,會影響BFRF1和Alix PRR功能區的結合能力 36 圖二、細胞內生性Alix與HA-BFRF1 mutants之分布情形 37 圖三、細胞內生性Emerin與HA-BFRF1 mutants之分布情形 38 圖四、以免疫沉澱法偵測BFRF1 mutants與Alix蛋白結合能力 39 圖五、BFRF1 inducible plasmid 轉染至T-REx HeLa 細胞,與藥物篩選後穩定細胞株的表現型態差異 40 圖六、當knockdown Chmp4B和Vps4A對於EBV 病毒複製與釋出的影響 41 圖七、當knockdown Chmp4A、Chmp4B、Chmp4C、Chmp6和 Chmp7 對於EBV 病毒複製與釋出的影響 42 圖八、當knockdown Vps4A、Chmp1B、Chmp2B和Chmp3 對於EBV 病毒複製與釋出的影響 43 圖九、於E. coli BL21中可表現His-BFRF1 蛋白,以尿素變性環境下純化His-BFRF1 蛋白 44 Table 45 表一、RNAi core盤式病毒詳細資訊 45 表二、ESCRT-III 利用siRNA使表現量下降或以domainant negative ESCRT-III 使功能異常時對各類病毒釋出量的影響 46 表三、ESCRT-III 利用siRNA使表現量下降時對細胞功能有影響的功能異常時對各類病毒釋出量的影響 47 5. 附錄 48 附錄一、人類單純皰疹病毒HSV進行出核的假說模型圖 48 附錄二、ESCRT 模組中個別蛋白的結合方式與組成示意圖 49 附錄三、HA-BFRF1 WT 及 deletion mutants和 Alix 三個功能區的結合能力 50 附錄四、BFRF1 與 Alix PRR 功能區結合需要仰賴 nucleic acid 51 6. 參考文獻 52 | |
dc.language.iso | zh-TW | |
dc.title | 探討 BFRF1 與ESCRT 模組在EB 病毒出核時所扮演
的角色與機制 | zh_TW |
dc.title | The role of BFRF1 and cellular ESCRT components in
regulating the nuclear egress of Epstein-Barr virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林素芳,李重霈,劉雅雯 | |
dc.subject.keyword | EB 病毒,BFRF1,核膜衍生液泡,出核過程,Alix,ESCRT, | zh_TW |
dc.subject.keyword | Epstein-Barr virus (EBV),BFRF1,nuclear envelope-derived vesicles,nuclear egress,Alix,ESCRT machinery, | en |
dc.relation.page | 61 | |
dc.identifier.doi | 10.6342/NTU201602235 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2016-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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