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系統識別號 U0026-1208201317423600
論文名稱(中文) 探討登革病毒非結構性蛋白NS5之小泛素化修飾於病毒複製中所扮演的角色
論文名稱(英文) Study the role of SUMO modification of dengue virus nonstructural protein 5 in viral replication
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 蘇展儀
研究生(英文) Chan-Yi Su
學號 s46004056
學位類別 碩士
語文別 中文
論文頁數 68頁
口試委員 指導教授-曾忠信
共同指導教授-賴明詔
口試委員-林以行
口試委員-劉校生
口試委員-蘇文琪
中文關鍵字 登革熱非結構蛋白NS5  小泛素化  小泛素化結合模體 
英文關鍵字 Dengue virus  NS5  SUMOylation  SUMO-interacting motif 
學科別分類
中文摘要 登革病毒 (Dengue virus, DENV)屬黃熱病毒科 (Flaviviridae),為帶有一單股正向核醣核酸的蚊媒病毒。登革病毒的基因可藉由轉譯及後續蛋白酶裁切過程,產生出十個病毒蛋白,其中三個為結構蛋白 (C, prM及Env),另外七個為非結構蛋白,包括NS1、NS2A、NS2B、NS3、NS4A、NS4B及NS5。小泛素化 (SUMOylation)為細胞中一種重要的蛋白質轉譯後修飾機制,參與許多細胞生理功能的調控,如蛋白質於細胞核質之分布、基因表現調控及訊息傳遞調控等等;此外有越來越多的研究指出,小泛素化修飾也參與在許多病毒感染的過程中。我們的研究發現,當細胞內小泛素化修飾過程中唯一的結合酵素Ubc9表現量改變時,登革病毒的複製能力也會受到影響,這意味著小泛素化修飾也參與在登革病毒的複製週期之中。為了進一步探討小泛素化修飾與登革病毒的複製的關係,我們藉由細胞內小泛素化分析 (In vivo SUMOylation assay)、細胞外小泛素化分析 (In vitro SUMOylation assay)及細胞內去小泛素化分析 (In vivo de-SUMOylation assay)等實驗,確認登革病毒的非結構蛋白NS5,亦即病毒的核醣核酸複製酶,是唯一會被小泛素化系統所修飾的登革病毒非結構蛋白。此外,我們建構了一系列的NS5區域性剔除突變株,並且利用它們進行後續之細胞內小泛素化分析實驗,我們發現小泛素化蛋白是針對NS5的N端甲基轉移酶 (methyltransferase)區段上離胺酸 (lysines)進行修飾;從點突變的結果發現,N端甲基轉移酶區段上的小泛素化結合模體 (SUMO-interacting motif, SIM)能夠影響小泛素化修飾NS5蛋白的能力。總結而論,我們的研究顯示,細胞中之小泛素化系統參與登革病毒的複製,我們亦發現登革病毒的NS5蛋白會被小泛素化系統所修飾。另外,NS5蛋白N端甲基轉移酶區段上的小泛素化結合模體的發現有助於我們接下來進一步探討NS5蛋白之小泛素化修飾如何調節登革病毒複製之分子機轉。
英文摘要 Dengue virus (DENV) is a single-stranded positive-sense RNA virus of the family Flaviviridae. The DENV genome encodes a single polyprotein precursor, which is processed into three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS4A, NS4B, and NS5). SUMO (Small ubiquitin-like modifier) has been identified as a reversible post-translational protein modifier. SUMOylation regulates a wide variety of cellular processes and plays important roles for numerous viruses during infection. In this study, we found that overexpression of Ubc9, the sole E2-conjugating enzyme required for protein SUMOylation, enhanced DENV replication whereas its knockdown reduced virus replication, suggesting that SUMOylation pathway is involved in DENV life cycle. We next carried out in vivo SUMOylation assay to search for the potential viral SUMO target(s). We found that DENV NS5 protein, the RNA-dependent RNA polymerase responsible for viral genome replication, is the only viral nonstructural protein which can be SUMOylated. Further, in vivo de-SUMOylation assay and in vitro SUMOylation assay were performed and confirmed that NS5 protein is a bona fide SUMO target. To delineate the region of NS5 protein in which the SUMO acceptor lysine(s) is located, expression plasmids for NS5 protein deletion mutants were generated and subjected to in vivo SUMOylation assay. We found that the SUMO acceptor sites are located in the N-terminal methyltransferase (MTase) domain of NS5 protein. Determination of the SUMOylated residues was elusive probably because of the presence of alternative SUMOylation sites. However, we found a SUMO-interacting motif (SIM) located in the MTase domain of NS5 protein and demonstrated that this SIM motif is required for NS5 protein SUMOylation. Collectively, these findings suggest that SUMOylation of NS5 protein is an important feature of DENV infection and may regulate viral replication.
論文目次 中文摘要 I
Abstract III
致謝 V
目錄 VI
圖示目錄 IX
列表目錄 X
緒論 1
一、登革病毒傳播及症狀 1
二、登革病毒簡介 1
三、登革病毒生活史 3
四、登革病毒逃脫先天免疫機制 3
五、登革病毒第五非結構蛋白 4
1. 蛋白質結構與功能 4
2. 登革病毒NS5蛋白的磷酸化修飾 5
3. 登革病毒NS5蛋白進入細胞核的作用 5
4. 與登革病毒NS5蛋白有交互作用的宿主蛋白 6
六、小泛素化蛋白 (SUMO) 7
七、小泛素化系統 7
八、小泛素化修飾功能 8
九、小泛素化結合模體 (SUMO-interacting motif) 9
十、小泛素化與病毒複製之關聯性 10
十一、登革病毒與小泛素化修飾 11
十二、研究動機及假設 11
材料與方法 13
一、細胞株及培養方式 13
二、病毒 13
三、質體DNA及siRNA 13
四、登革病毒蛋白表現質體及其衍生之區域性剔除突變株建構 14
五、登革病毒蛋白表現質體之點突變株建構 16
1. Site-direct mutagenesis 16
2. Jumping PCR 16
六、大量質體DNA製備 17
七、細胞轉染質體DNA 18
八、細胞外小泛素化修飾法 18
九、細胞內小泛素化修飾法 19
十、細胞轉染siRNA 19
十一、登革病毒感染 20
十二、免疫沉澱法 20
十三、西方點墨法 21
十四、病毒溶斑分析法 22
十五、免疫螢光染色 22
十六、冷光酶分析 23
十七、抗體 23
十八、數據分析 24
十九、引子 24
實驗結果 25
一、小泛素化系統參與在登革病毒的複製週期中 25
二、小泛素化系統影響登革病毒次基因體複製子之複製 25
三、搜尋受小泛素化系統所修飾之登革病毒蛋白 26
四、登革病毒NS5蛋白與Ubc9共同聚集於細胞核內 27
五、確認小泛素化系統修飾登革病毒NS5蛋白 27
六、小泛素化系統修飾登革病毒所產出之NS5蛋白 28
七、第二及第三型登革病毒之NS5蛋白皆能被小泛素化修飾 29
八、登革病毒NS5蛋白中之高保留度離胺酸不影響小泛素化修飾NS5蛋白 29
九、小泛素化蛋白結合於NS5的N端甲基轉移酶區段 30
十、確認預測之區段為小泛素化蛋白結合區段 30
十一、小泛素化結合模體 (SUMO-interacting motif)影響小泛素化修飾NS5蛋白 31
十二、小泛素化修飾不影響NS5是否進入細胞核 32
十三、結論 32
討論 33
參考文獻 40
圖示 48
列表 64
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