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腸病毒71型 (EV71) 基因體的五端非轉譯區中包含了對於病毒蛋白質轉譯作用不可或缺的 internal ribosome entry site (IRES) 結構。由於病毒本身核糖核酸基因體所能攜帶的遺傳信息有限，EV71 和其他小 RNA 科病毒會藉由利用宿主因子，稱為 IRES trans-acting factors (ITAFs)，來協助進行 IRES-dependent 的轉譯作用。在此研究中，我們揭露了EV71的病毒蛋白酶 2A 能夠切割細胞蛋白質 far upstream element-binding protein 1 (FBP1) ; 先前研究已知此蛋白質能直接結合到EV71 五端非轉譯區的linker region中並藉此來促進 IRES-driven 的轉譯作用。在EV71感染過程中，FBP1 的 Gly-371 residue 會受到病毒蛋白酶2A的切割並因此產生一個具有功能的切割產物，FBP11-371。有趣的是，此切割產物 FBP11-371 能促進病毒的IRES活性。Footprinting 分析與凝膠遷移實驗顯示 FBP11-371 與 FBP1 相類似會結合到 EV71 五端非轉譯區的 linker region 但在確切的結合位點上與FBP1 卻不同。我們更進一步地發現當 FBP1與 FBP11-371同時結合到linker region時，能加成地促進 IRES-driven 的轉譯作用與成熟病毒顆粒的產量。我們的研究結果拓展了此領域對病毒-宿主相互作用、病毒如何利用與調控 ITAFs 的理解，同時對於病毒自身蛋白質轉譯作用上的調控提供了新的見解。

The 5' untranslated region (5' UTR) of the enterovirus 71 (EV71) RNA genome contains an internal ribosome entry site (IRES) that is indispensable for viral protein translation. Due to the limited coding capacity of their RNA genomes, EV71 and other picornaviruses typically recruit host factors, known as IRES trans-acting factors (ITAFs), to mediate IRES-dependent translation. Here, we show that EV71 viral proteinase 2A is capable of cleaving far upstream element-binding protein 1 (FBP1), a positive ITAF that directly binds to the EV71 5' UTR linker region to promote viral IRES-driven translation. The cleavage occurs at the Gly-371 residue of FBP1 during the EV71 infection process, and this generates a functional cleavage product, FBP11-371. Interestingly, the cleavage product acts to promote viral IRES activity. Footprinting analysis and gel mobility shift assay results showed that FBP11-371 similarly binds to the EV71 5' UTR linker region, but at a different site from full-length FBP1; moreover, FBP1 and FBP11-371 were found to act additively to promote IRES-mediated translation and virus yield. Our findings expand the current understanding of virus-host interactions with regard to viral recruitment and modulation of ITAFs, and provide new insights into translational control during viral infection.

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誌謝 iii
中文摘要 iv
Abstract v
Table of Contents vi
Table of Figures viii
1. Introduction 1
1.1 Classification and Epidemiology 1
1.2 Virion structure 2
1.3 Genome organization 2
1.4 The internal ribosome entry site and cellular factors involved in viral translation 4
1.5 Viral RNA synthesis and RNA replication 6
1.6 Effects of viral proteinases on the host cells 8
1.5 Characterization of the cellular ITAF: Far upstream element-binding protein 1 (FBP1) 9
1.6 Objective of the study: The role of FBP1 and its cleavage products in EV71 replication 10
2. Materials and Methods 11
2.1 Infection of RD cells and cell lysate preparation 11
2.2 Plasmids and constructs 12
2.3 Expression and purification of recombinant proteins 15
2.4 Coupled transcription/translation of [35S] methionine-labeled proteins 16
2.5 In vitro proteinase cleavage assay 16
2.6 Immunoblot analysis 16
2.7 In vitro transcription 17
2.8 Pull-down assay for biotinylated EV71 5′ UTR RNA with streptavidin beads 18
2.9 Enzymatic RNA footprinting 19
2.10 In vitro translation assay 19
2.11 Lentiviral vector preparation 20
2.12 Gel mobility assays and preparation of labeled RNA probes 20
2.13 RNP immunoprecipitation 21
2.14 Reverse-phase liquid chromatography (RPLC) and mass spectrometry (MS) 22
2.15 Database searching for peptide identification 23
2.16 Reagents 24
2.17 Statistical analysis 24
3. Results 25
3.1 Cleavage of FBP1 during EV71 infection 25
3.2 FBP1 cleavage is independent of proteasome, lysosome, and caspase activities 26
3.3 Cleavage of FBP1 by EV71 viral proteinase 2A in vitro 27
3.4 Mapping the EV71 2Apro cleavage site in FBP1 29
3.5 Association of FBP1, FBP11-371 and EV71 5′ UTR RNA 31
3.6 FBP11-371 acts as an additive ITAF to enhance viral IRES activity 35
4. Discussion 38
5. References 44
6. Figures and Tables 58
Fig 1. Function, expression and subcellular localization of FBP1 in EV71-infected cells. 58
Fig 2. FBP1 cleavage following EV71 infection is independent of cellular proteasome, lysosome, or caspase activities. 60
Fig 3. In vitro induction of FBP1 cleavage by EV71 viral proteinase 2A. 61
Fig 4. Determining the EV71 2Apro primary cleavage site in FBP1.
63
Fig 5. Confirmation of FBP1 cleavage at Gly-371 by EV71 2Apro. 66
Fig 6. Association between FBP1, FBP11-371, and the EV71 5′ UTR. 68
Fig 7. Additive effects of FBP1 and FBP11-371 on IRES-driven translation. 69
Fig 8. Binding competition between FBP1, FBP11-371 and PTB to EV71 5′ UTR RNA and the effect of FBP1 and FBP11-371 on EMCV IRES-driven translation in vitro. 72
Fig 9. Proposed model for the functions of FBP1 and FBP1-371 in EV71 IRES-driven translation. 73
7. Appendix 74
Fig A.1 Confirmation of FBP1 cleavage site by in vitro cleavage assay and LC-MS/MS. 74
Fig A.2 Association of FBP1 and FBP11-371 with EV71 5′ UTR in in infected cells. 75
Fig A.3 Binding position of FBP1 and FBP11-371 within EV71 5′ UTR linker region RNA. 76


Table of Figures
Fig 1. Function, expression and subcellular localization of FBP1 in EV71-infected cells.
..........................................................................................................................................58
Fig 2. FBP1 cleavage following EV71 infection is independent of cellular proteasome,
lysosome, or caspase activities.........................................................................................60
Fig 3. In vitro induction of FBP1 cleavage by EV71 viral proteinase 2A. ......................61
Fig 4. Determining the EV71 2Apro primary cleavage site in FBP1. ...........................63
Fig 5. Confirmation of FBP1 cleavage at Gly-371 by EV71 2Apro..................................66
Fig 6. Association between FBP1, FBP11-371, and the EV71 5′ UTR. ..........................68
Fig 7. Additive effects of FBP1 and FBP11-371 on IRES-driven translation. ...................69
Fig 8. Binding competition between FBP1, FBP11-371 and PTB to EV71 5′ UTR RNA
and the effect of FBP1 and FBP11-371 on EMCV IRES-driven translation in vitro. ........72
Fig 9. Proposed model for the functions of FBP1 and FBP1-371 in EV71 IRES-driven
translation.........................................................................................................................73

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