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系統識別號 U0026-2603201502415400
論文名稱(中文) 利用醣蛋白質體學導向模式尋找新的腸病毒71型相關性蛋白
論文名稱(英文) Identification of novel EV71-interacting proteins by glycoproteomic approaches
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 蘇珮誼
研究生(英文) Pei-Yi Su
電子信箱 s5897114@mail.ncku.edu.tw
學號 S58971146
學位類別 博士
語文別 英文
論文頁數 168頁
口試委員 指導教授-張權發
召集委員-王貞仁
口試委員-葉才明
口試委員-劉校生
口試委員-洪錦堂
口試委員-周彥宏
中文關鍵字 腸病毒71型  細胞受體  核仁蛋白  醣蛋白質體學  唾液酸 
英文關鍵字 Enterovirus 71  Receptor  Nucleolin  Glycoproteomic  Sialic acid 
學科別分類
中文摘要 腸病毒71型 (EV71)是一主要感染嬰幼兒可引發手足口症及嚴重神經性病變的致病源。儘管兩個具高度醣化的膜蛋白SCARB2(巨噬细胞消除受体B2型)及PSGL-1 (P選擇素糖蛋白配體1) 被證實為EV71的細胞或功能性受體,但EV71的致病機轉仍舊無法清楚了解。醣化作用在病毒感染時參與的角色曾經在其他微小核糖核酸病毒研究中被討論。基於前述,本篇研究中我們首先針對細胞膜上的唾液酸化可影響EV71與蛋白的辨識能力進行分析,並證實去唾液酸化可降低EV71-SCARB2的結合能力。再者,腸病毒71型具多細胞受體的特性也曾經被提及,這也意謂細胞膜上仍具有未被發現的腸病毒71型相關蛋白參與病毒染感的過程。因此,我們利用醣蛋白質體導向模式找尋新的EV71相關蛋白並釐清其在EV71染感中扮演的角色。我們分離與EV71具相聯性的唾液酸化膜蛋白進行蛋白質體分析,利用LC MS/MS 蛋白質體分析中有十六個蛋白被鑑定。而其中我們選擇細胞表面上的核仁蛋白 (Nucleolin) 深入探討,我們發現EV71可直接藉由其外鞘蛋白VP1與核仁蛋白結合。若抑制細胞膜上核仁蛋白表面可減低EV71與人類細胞結合、感染能力以及病毒毒性。此外,高度表現人類核仁蛋白在老鼠細胞上可增加EV71黏合及進入細胞的能力。另一方面,我們發現細胞膜上核仁蛋白、乳鐵蛋白、胞漿素原及SCARB2或許可能形成一個複合體而幫助病毒的進入。我們的結果證實人類核仁蛋白可被EV71視為結合受體而幫助病毒感染。本篇研究不僅提供在了解EV71早期感染過程中釐清病毒受體的結合機制,更證實醣蛋白質體學可被當作是一探索新病原菌相關性蛋白的方式。
英文摘要 Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD). EV71 infection of the central nervous system (CNS) causes severe neurological complications in infants. Although two highly glycosylated membrane proteins, SCARB2 and PSGL-1, have been identified as the cellular and functional receptors of EV71, the pathogenesis of EV71 remains mostly ambiguous. The influence of glycosylation on viral infections has been discussed in relation to other picornaviruses. Based on these previous findings, we first attempted to establish whether cell surface sialylation can mediate EV71-protein recognition and to determine whether the interaction between SCARB2 and EV71 is retarded after desialylation. Second, the multiple receptor characteristics of EV71 have been explored, and it has been suggested that there are unknown EV71-interacting proteins on the cell surface which are involved in the attachment and infection of EV71. We therefore applied glycoproteomic approaches to identify novel EV71-interacting proteins and to verify the roles of candidate proteins in EV71 binding and infection. We isolated the EV71-associated glycoproteins for the purpose of protein identification. Among the sixteen proteins identified using LC MS/MS spectrometry analysis, we selected cell-surface nucleolin for in-depth analysis. We found that EV71 interacts directly with nucleolin via the VP1 capsid protein. In addition, it was found that the knockdown of cell surface nucleolin decreased EV71 binding, infection, as well as viral infectivity in human cells. In addition, over-expression of human nucleolin on the surface of murine cells increased EV71 attachment and entry. Furthermore, we found that the surface nucleolin, lactoferrin, and plasminogen may associate with SCARB2 and assist EV71 infection. Our data strongly suggest that human nucleolin is an receptor for EV71 infection. Our work not only contributes to an understanding of virus-receptor interactions in the early stages of EV71 infection, but also demonstrates that glycoproteomic technology is a reliable methodology by which to discover novel pathogen-associated proteins.
論文目次 English Abstract I
Chinese Abstract III
Acknowledgement V
Abbreviations VI
Index VIII
Figure Index XI
Table Index XIII
Appendix Index XIV
Introduction 1
Enterovirus 71 1
The entry of Picornaviridae 3
Receptors for Picornaviridae 4
Glycosylation mediates virus attachment 7
Glycoproteomics 8
Objective, specific aims and experimental design 11
Materials and Methods 15
1. Cell culture and virus propagation 15
2. EV71-associated sialylated membrane protein collection 16
2.1 Sialylated membrane isolation 16
2.2 EV71-interacting protein immunoprecipitation after de-sialylation 17
2.3 Silver staining 18
2.4 Protein identification 18
3. EV71-proteins interaction 19
3.1 Virus Overlaying Protein Binding Assay (VOPBA) 19
3.2 Enzyme-Linked Immunosorbent Assay (ELISA) 20
3.3 Immunofluorescence assay 20
4. Plasmid Construction and Transfection 21
4.1 sh-RNA plasmids transfection 21
4.2 Overexpression of hNCL in NIH-3T3 and L929 cells 22
5. Virus binding and infection 22
5.1 Antibody blocking for Flow cytometry 22
5.2 Virus binding assay for flow cytometry 23
5.3 Virus binding assay for Q-PCR 23
5.4 Virus binding assay for Western blotting 24
5.5 Virus binding for plaque assay/ CCID50 24
6. Flow Cytometry 25
7. Western Blotting 25
8. Observation of cytopathic effects 25
9. Animal model for EV71 infection 26
10. Statistical analysis 26
Results 27
Role of sialylation in EV71 attachment 27
Membrane sialylated-proteins isolation 28
Investigation of sialylated protein-EV71 association 28
Identification of EV71-interacting glycoproteins 29
The effects of NCL knockdown in the attachment and entry of EV71 to host cells 32
The effects of human NCL expression in the attachment and infection of EV71 to non-susceptible cells 34
The interaction of NCL and SCARB2 during EV71 infection 37
The roles of plasminogen (PLG) in EV71 infection 38
Discussion 41
Conclusions 51
References 53
Instruments and Reagents 119
Curriculum Vitae VI
Publications IX
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