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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97477完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張麗冠 | zh_TW |
| dc.contributor.advisor | Li-Kwan Chang | en |
| dc.contributor.author | 郭姿筠 | zh_TW |
| dc.contributor.author | Tzu-Yun Kuo | en |
| dc.date.accessioned | 2025-06-18T16:19:10Z | - |
| dc.date.available | 2025-06-19 | - |
| dc.date.copyright | 2025-06-18 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-05-28 | - |
| dc.identifier.citation | 1. Zamora MR. DNA Viruses (CMV, EBV, and the Herpesviruses). Semin Respir Crit Care Med. 2011;32(04):454-70. doi: 10.1055/s-0031-1283285.
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The crucial regulatory role of type I interferon in inflammatory diseases. Cell Biosci. 2023;13(1):230. doi: 10.1186/s13578-023-01188-z. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97477 | - |
| dc.description.abstract | EB 病毒 (Epstein-Barr Virus, EBV) 又稱為第四型人類皰疹病毒，全球約有 90% 以上的人受到感染，與多種癌症和自體免疫疾病相關。EB 病毒的生活史分為潛伏期 (latency) 與溶裂期 (lytic cycle)，甫進入溶裂期時會表現極早期蛋白質 Rta，主要作為轉錄因子調控早期與晚期基因表達，使病毒能複製基因體與製造 殼體蛋白質，進而組裝並釋放病毒顆粒。病毒感染時，宿主可以感應細胞質中的 外源病毒 DNA 或因壓力釋出的內源性胞器 DNA，透過 cGAS-STING 訊息傳遞 路徑產生第一型干擾素 (type I interferons)，以調節先天免疫反應。先前研究指出 Rta 會減少由 cGAS-STING 引起的第一型干擾素基因的轉錄。本研究先以 luciferase reporter assay 與定量反轉錄 PCR (RT-qPCR) 確認 Rta 能減少第一型干擾素基因轉錄以及所傳遞的下游免疫反應；並發現 Rta 的蛋白質量增加時，會減少細胞中過量表達的 STING 與免疫反應最下游的磷酸化 IRF3 蛋白質的表現量。接著以 cycloheximide (CHX) chase assay 確認 Rta 會透過增強 STING 蛋白質的細胞自噬 (autophagy)，降低 STING 的穩定性。本研究進一步以免疫共沈澱分析證實 Rta 會與 STING 蛋白質結合，並且發現 Rta 可以減少 STING 在內質網 (endoplasmic reticulum)上形成二聚體和多聚體。此外以變性蛋白免疫沈澱 (denaturing-immunoprecipitation) 分析，顯示 Rta 會干擾 STING 的 K63 鏈結的泛素化 (ubiquitination)，進而影響其功能調節。本研究證實 Rta 可以促進 STING 的細胞自噬降解以及干擾 STING 的泛素化，來抑制 cGAS-STING 訊息傳遞所引起的第一型干擾素先天免疫反應。 | zh_TW |
| dc.description.abstract | Epstein-Barr Virus (EBV), or human herpesvirus 4 (HHV4), infects 90% of the adult population worldwide and is associated with cancers, autoimmune diseases, and neurological disorders. The EBV life cycle is split into latency and the lytic phases; the immediate-early protein Rta expressed at lytic initiation transactivates the expression of EBV early and late genes, facilitating viral DNA replication, production of viral structural proteins, and virion assembly and egress. It is well known that viral DNA or DNA released from organelles triggers cGAS-STING signaling and ultimately activates the transcription of type I-interferon (IFN) genes to promote innate immunity. Previous research revealed that EBV Rta reduces the cGAS-STING-induced IFN-b promoter activities, although the underlying mechanism remains unclear. This study first confirmed that Rta decreased the transcription of the IFN-b gene and interferon-stimulated genes (ISGs). Rta also reduces the levels of STING and phosphorylated IRF3 in a dose-dependent manner, as Rta destabilizes STING by enhancing its autophagic degradation in a cycloheximide (CHX) chase assay. This study also shows the interaction between Rta and STING and that Rta reduces the formation of STING dimers and oligomers on the endoplasmic reticulum (ER) surface, which is critical to cGAS-STING signaling. Meanwhile, Rta perturbs total ubiquitination and K63-linked polyubiquitination on STING, possibly affecting STING functionalities. These findings illuminate Rta’s importance in regulating the cGAS-STING-mediated type I IFN response by promoting STING autophagic degradation and perturbing STING K63-linked polyubiquitination. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-06-18T16:19:10Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-06-18T16:19:10Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii Abstract iv Table of Contents vi Tables ix Figures x 1 Introduction 1 1.1 Epstein-Barr Virus (EBV) 1 1.1.1 Taxonomy and Epidemiology 1 1.1.2 EBV Structure and Nomenclature of EBV Genes 1 1.1.3 The EBV Life Cycle 2 1.1.4 The EBV Immediate-early Genes BRLF1 and BZLF1 4 1.1.5 The EBV Rta Protein 5 1.2 The Type I Interferon (IFN) Response and cGAS-STING Pathway 6 1.2.1 Induction and Signaling of Type I IFNs 6 1.2.2 The cGAS-STING Pathway 8 1.2.3 The STING Protein 10 1.2.4 Post-translational Modifications (PTMs) of STING Activity 11 1.3 Modulation of the cGAS-STING Pathway by EBV 12 1.4 Motivation and Specific Aims 13 2 Materials and Methods 15 2.1 Cell Lines 15 2.2 Plasmids 15 2.3 Plasmid Extraction 15 2.4 Plasmid Construction, Transformation, and Quick-Screening 16 2.5 Transfection 17 2.6 Cell Lysate Preparation 17 2.7 SDS-PAGE and Western blotting 18 2.8 Luciferase Reporter Assay 19 2.9 RNA extraction and RT-qPCR 20 2.10 Cycloheximide (CHX) Chase Assay 21 2.11 Immunoprecipitation (IP) 21 2.12 Quantitation and Statistical Analysis 22 3 Results 23 3.1 Rta suppressed the cGAS-STING-induced type I IFN response 23 3.2 Rta reduced STING proteins and suppressed the cGAS-STING-mediated type I IFN response in a dose-dependent manner 24 3.3 Rta caused STING degradation through the autophagic pathway 25 3.4 Interaction between Rta and STING 26 3.5 Rta reduced the formation of STING dimers and oligomers 27 3.6 Rta perturbed STING ubiquitination 28 4 Discussion 31 4.1 Rta suppressed the cGAS-STING-mediated immune response 31 4.2 Rta destabilized STING and reduced STING protein levels 32 4.3 Rta strengthened the autophagic degradation of STING 33 4.4 The importance of STING-ubiquitin modulation by Rta 34 4.5 Limitations of this Study and future work for investigating EBV-positive cell lines 36 4.6 Conclusion 37 5 Tables 38 6 Figures 42 7 References 52 8 Appendix 77 | - |
| dc.language.iso | en | - |
| dc.title | EB 病毒 Rta 於 cGAS-STING 先天免疫反應中所扮演的角色 | zh_TW |
| dc.title | Role of Epstein-Barr Virus Rta in cGAS-STING-mediated Innate Immunity | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 劉世東;陳美如;邱亞芳;劉旻禕 | zh_TW |
| dc.contributor.oralexamcommittee | Shih-Tung Liu;Mei-Ru Chen;Ya-Fang Chiu;Helene Minyi Liu | en |
| dc.subject.keyword | EB 病毒,Rta,先天免疫,第一型干擾素,cGAS-STING 訊息傳遞, | zh_TW |
| dc.subject.keyword | Epstein-Barr Virus,Rta,innate immunity,type I interferons,cGAS-STING pathway, | en |
| dc.relation.page | 80 | - |
| dc.identifier.doi | 10.6342/NTU202500999 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-05-28 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2030-05-27 | - |
| 顯示於系所單位： | 生化科技學系 | |
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