臺灣博碩士論文加值系統

Far upstream element-binding protein 2 (FBP2)是一個internal ribosomal entry site (IRES) trans-acting factor (ITAF)，FBP2結合至腸病毒71型的醣體結合區(internal ribosomal entry site) 並且抑制腸病毒71型的轉譯。我們在腸病毒71型感染的細胞中發現FBP2被切割。活的病毒和replicon都可以引發FBP2的切割，但經過紫外線照後後失去複製能力的病毒顆粒無法引發FBP2的切割。實驗結果顯示腸病毒71型感染所引起的proteasome，autophagy，還有caspase activity都有參予FBP2的切割。為了尋找FBP2的切割位點，我們將FLAG peptide接在FBP2的N端或C端並利用FLAG抗體去偵測FBP2的切割片段。最後我們發現了一個失去carboxyl-terminus的FBP2的切割片段 會正向的調控EV71的轉譯。本篇研究發現病毒感染後引發一些細胞內的活動，這些活動導致了一個病毒負調控因子的切割。

Far upstream element-binding protein 2 (FBP2) is an internal ribosomal entry site (IRES) trans-acting factor (ITAF) that negatively regulates enterovirus 71 (EV71) translation. This study shows that EV71 infection cleaved FBP2. Live EV71 and the EV71 replicon (not UV-inactivated virus particles) induced FBP2 cleavage, suggesting that viral replication results in FBP2 cleavage. The results also showed that virus-induced proteasome, autophagy, and caspase activity co-contribute to EV71-induced FBP2 cleavage. Using FLAG-fused FBP2, we mapped the potential cleavage fragments of FBP2 in infected cells. We also found that FBP2 altered its function when its carboxyl-terminus was cleaved. This study presents a mechanism for virus-induced cellular events to cleave a negative regulator for viral IRES-driven translation.

目錄

指導教授推薦書
口試委員會審定書
國家圖書館博士論文電子檔案上網授權書 III
長庚大學博士論文著作授權書 IV
致謝 V
中文摘要 VI
ABSTRACT VII
目錄 VIII
圖表目錄 X
CHAPTER 1 INTRODUCTION - 1 -
1.1 EPIDEMIOLOGY - 1 -
1.2 CLASSIFICATION - 1 -
1.3 CHARACTERIZATION INTERNAL RIBOSOMAL ENTRY SITE (IRES) TRANS-ACTING FACTOR - 3 -
1.4 FUNCTIONS OF FAR UPSTREAM ELEMENT-BINDING PROTEIN 2 - 4 -
1.5 SPECIFIC AIMS : THE MECHANISMS OF EV71 INFECTION INDUCES FBP2 TRUNCATION AND THE FUNCTIONS OF TRUNCATED FBP2 - 5 -
CHAPTER 2 MATERIAL AND METHODS - 7 -
2.1 CELL LINES AND VIRUS INFECTION - 7 -
2.2 REAGENTS - 8 -
2.3 PLASMID CONSTRUCTION AND EXPRESSION - 8 -
2.4 CONSTRUCTION AND EXPRESSION OF EV71 REPLICON - 11 -
2.5 CONSTRUCTION AND PURIFICATION OF RECOMBINANT PROTEIN - 12 -
2.6 WESTERN BLOTTING ANALYSIS - 14 -
2.7 35S-METHIONINE/CYSTEINE-LABELING ASSAY - 15 -
2.8 IN VITRO PROTEASE CLEAVAGE ASSAY - 16 -
2.9 IN VIVO UBIQUITINATION ASSAY - 17 -
2.10 PREPARATION OF CELL EXTRACTS - 17 -
2.11 IN VITRO TRANSCRIPTION - 18 -
2.12 PULL DOWN ASSAY OF STREPTAVIDIN BEADS AND BIOTINYLATED RNA - 19 -
2.13 PREPARATION OF HELA CELLS TRANSLATION EXTRACTS - 19 -
2.14 IN VITRO TRANSLATION ASSAY - 20 -
2.15 SUCROSE GRADIENT FRACTIONATION - 20 -
CHAPTER 3 RESULTS - 22 -
3.1 EV71 INFECTION INDUCES FBP2 TRUNCATION - 22 -
3.2 TRUNCATION OF FBP2 IS ASSOCIATED WITH EV71 REPLICATION - 23 -
3.3 INVOLVEMENT OF VIRUS-INDUCED AUTOPHAGY, LYSOSOME AND PROTEASOME IN FBP2 TURNOVER - 25 -
3.4 VIRUS-INDUCED CASPASE ACTIVITY CLEAVES FBP2 - 27 -
3.5 FBP2 IS CLEAVED FROM BOTH AMINE (N) AND CARBOXYL (C) TERMINUS - 29 -
3.6 DISTRIBUTION OF FBP2 AND TRUNCATED FBP2 DURING EV71 INFECTION - 31 -
3.7 FBP21-503 POSITIVELY REGULATED EV71 IRES ACTIVITY - 31 -
3.8 FBP21-503 COMPETED THE BINDING OF FBP1 TO EV71 5’ UTR - 34 -
3.9 EFFECT OF FBP2 AND FBP21-503 ON RIBOSOME PROFILING - 34 -
CHAPTER 4 DISCUSSION - 36 -
REFERENCES - 41 -
FIGURES - 55 -

圖表目錄

FIGURE 1. FUNCTION AND TRUNCATION OF FBP2 IN EV71-INFECTED CELLS. - 55 -
FIGURE 2. TRUNCATION OF FBP2 WAS ASSOCIATED WITH EV71 REPLICATION. - 57 -
FIGURE 3. INVOLVEMENT OF PROTEASOME, LYSOSOME, AND AUTOPHAGY IN FBP2 TURNOVER. - 59 -
FIGURE 4. INVOLVEMENT OF CASPASE ACTIVITY IN FBP2 CLEAVAGE. - 61 -
FIGURE 5. FBP2 WAS CLEAVED FROM BOTH THE N AND C TERMINUS. - 63 -
FIGURE 6. DISTRIBUTION OF FBP2 AND TRUNCATED FBP2. - 65 -
FIGURE 7. FBP21-503 POSITIVELY REGULATED EV71 IRES ACTIVITY. - 66 -
FIGURE 8. FBP21-503 COMPETED THE BINDING OF FBP1 TO EV71 5’ UTR - 68 -
FIGURE 9. DIFFERING CO-SEDIMENTATION FOR RIBOSOMAL SUBUNIT PROTEINS FOR FBP2 AND FBP21-503 IN EV71-INFECTED CELLS - 69 -
FIGURE 10. EV71 INFECTION INDUCES FBP2 CLEAVAGE AND CONVERTS IT TO A POSITIVE REGULATOR. - 70 -

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