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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳美如 | zh_TW |
| dc.contributor.advisor | Mei-Ru Chen | en |
| dc.contributor.author | 張景竣 | zh_TW |
| dc.contributor.author | Ching-Chun Chang | en |
| dc.date.accessioned | 2025-09-22T16:09:20Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-30 | - |
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J Gen Virol, 91(Pt 9), 2186-96. 10.1099/vir.0.019729-0. Wang, J. T., Yang, P. W., Lee, C. P., Han, C. H., Tsai, C. H. & Chen, M. R. (2005) Detection of Epstein-Barr virus BGLF4 protein kinase in virus replication compartments and virus particles. J Gen Virol, 86(Pt 12), 3215-3225. 10.1099/vir.0.81313-0. Wang, W. H., Chang, L. K. & Liu, S. T. (2011) Molecular interactions of Epstein-Barr virus capsid proteins. J Virol, 85(4), 1615-24. 10.1128/jvi.01565-10. Wang, W. H., Kuo, C. W., Chang, L. K., Hung, C. C., Chang, T. H. & Liu, S. T. (2015) Assembly of Epstein-Barr Virus Capsid in Promyelocytic Leukemia Nuclear Bodies. J Virol, 89(17), 8922-31. 10.1128/jvi.01114-15. Westphal, E. M., Mauser, A., Swenson, J., Davis, M. G., Talarico, C. L. & Kenney, S. C. (1999) Induction of lytic Epstein-Barr virus (EBV) infection in EBV-associated malignancies using adenovirus vectors in vitro and in vivo. Cancer Res, 59(7), 1485-91. Yang, Y., Guo, L., Chen, L., Gong, B., Jia, D. & Sun, Q. (2023) Nuclear transport proteins: structure, function, and disease relevance. Signal Transduct Target Ther, 8(1), 425. 10.1038/s41392-023-01649-4. Yokoyama, N., Fujii, K., Hirata, M., Tamai, K., Kiyono, T., Kuzushima, K., Nishiyama, Y., Fujita, M. & Tsurumi, T. (1999) Assembly of the epstein-barr virus BBLF4, BSLF1 and BBLF2/3 proteins and their interactive properties. J Gen Virol, 80 ( Pt 11), 2879-2887. 10.1099/0022-1317-80-11-2879. Young, L. S., Arrand, J. R. & Murray, P. G. (2007) EBV gene expression and regulation. In: Arvin, A., Campadelli-Fiume, G., Mocarski, E., Moore, P. S., Roizman, B., Whitley, R. & Yamanishi, K. (eds.) Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press Copyright © Cambridge University Press 2007. Yu, V. Z., Wong, V. C., Dai, W., Ko, J. M., Lam, A. K., Chan, K. W., Samant, R. S., Lung, H. L., Shuen, W. H., Law, S., Chan, Y. P., Lee, N. P., Tong, D. K., Law, T. T., Lee, V. H. & Lung, M. L. (2015) Nuclear Localization of DNAJB6 Is Associated With Survival of Patients With Esophageal Cancer and Reduces AKT Signaling and Proliferation of Cancer Cells. Gastroenterology, 149(7), 1825-1836.e5. 10.1053/j.gastro.2015.08.025. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99962 | - |
| dc.description.abstract | EB病毒 (Epstein-Barr virus) 在感染細胞，進入溶裂期時，有多種缺乏典型核定位訊號 (nuclear localization signal) 的病毒蛋白仍必須進入細胞核才能執行功能。本研究發現宿主的HSP70共伴侶蛋白DNAJB6a是其中EB病毒引子酶BSLF1關鍵的入核調控因子。我們證實DNAJB6a可直接與BSLF1結合，並將其運送至細胞核內；相對地，其細胞質型的同種異構物DNAJB6b則無法執行此功能。BSLF1依賴DNAJB6a入核的過程，不僅依賴DNAJB6a本身的核定位能力，也需要其招募HSP70 (特別是HSPA1A) 的功能。當細胞中DNAJB6a缺失時，即使BSLF1與解旋酶-引子酶複合體成員共表現時具有部分入核的能力，BSLF1的入核能力仍受阻，導致病毒DNA複製減少以及病毒粒子釋放顯著下降。除了在病毒早期複製階段的角色外，DNAJB6a在EBV後期的組裝過程也發揮關鍵的功能。我們的結果顯示，攜帶NLS的病毒次要衣殼蛋白BORF1與DNAJB6a會一同被招募至PML核小體。這些結構被認為是EB病毒衣殼組裝的場所。DNAJB6a與BORF1形成複合體，並可能藉由HSPA1A穩定BORF1蛋白；反之，當細胞缺乏DNAJB6a時，BORF1會出現錯誤定位並快速降解，可能干擾病毒衣殼的正常形成。而DNAJB6a的過度表現則會提升BORF1表現量並促進較大的BORF1核內點狀結構生成，此作用亦依賴其與HSP70結合的能力。除此之外，我們進一步提出BSLF1藉DNAJB6a的幫助進入細胞核後EB病毒的蛋白激酶BGLF4可能藉由競爭BSLF1與DNAJB6a的結合幫助BSLF1從細胞核膜附近重新分布至病毒複製區域。綜合而言，本研究揭示DNAJB6a在EB病毒溶裂期中具備雙重功能：協助病毒複製酶進入細胞核，並協調病毒衣殼在細胞核內的組裝。我們的結果凸顯 EBV 如何挾持宿主伴侶蛋白，以精準調控其生命週期中的關鍵步驟。 | zh_TW |
| dc.description.abstract | During Epstein-Barr virus (EBV) lytic reactivation, several viral proteins lacking classical nuclear localization signals (NLS) must still translocate into the nucleus to perform their functions. In this study, we identify the host HSP70 co-chaperone DNAJB6a as a key mediator of nuclear import for the viral primase BSLF1. We demonstrate that DNAJB6a directly binds BSLF1 and facilitates its nuclear entry, whereas the cytosolic isoform DNAJB6b fails to do so. This nuclear import process requires both the nuclear localization capacity of DNAJB6a and its ability to recruit HSP70, particularly HSPA1A. Notably, depletion of DNAJB6a impairs BSLF1 nuclear accumulation even when its helicase-primase complex partners are co-expressed, leading to reduced viral DNA replication and markedly diminished virion release. Beyond its role in early replication, DNAJB6a also contributes to the late phase of viral assembly. We show that BORF1, a minor capsid protein bearing an NLS, recruits DNAJB6a to promyelocytic leukemia (PML) nuclear bodies, which serve as assembly hubs for EBV capsids. DNAJB6a forms a complex with BORF1 and may stabilize the BORF1 protein through HSPA1A. In contrast, DNAJB6a depletion results in BORF1 mislocalization and rapid degradation, likely disrupting capsid formation. Overexpression of DNAJB6a enhances BORF1 protein levels and promotes the formation of larger nuclear puncta, an effect dependent on its HSP70-binding activity. Furthermore, we propose that once BSLF1 enters the nucleus via DNAJB6a, the viral kinase BGLF4 may facilitate its redistribution from the nuclear rim to replication compartments by displacing DNAJB6a. Together, our findings reveal a dual role for DNAJB6a in EBV lytic replication: directing nuclear import of a key viral replication enzyme and coordinating capsid assembly within the nucleus. This study highlights how EBV hijacks host chaperone machinery to precisely orchestrate critical stages of its life cycle. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:09:20Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:09:20Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iv Abstract vi Chapter 1: Introduction 1 1.1 Epstein-Barr virus 1 1.1.1 Classification and associated diseases 1 1.1.2 EBV structure and genome 2 1.1.3 EBV life cycle 3 1.2 Molecular chaperone 5 1.2.1 Classification and functions of HSP families 5 1.2.2 Characterization and functions of DNAJB6 8 1.2.3 Degradation pathways in protein quality control 10 1.3 Nuclear Transport of Epstein-Barr Virus Proteins 13 1.3.1 Mechanisms of nuclear import in eukaryotic cells 13 1.3.2 EBV Proteins that require nuclear localization 14 1.4 Replication compartment 15 1.4.1 Definition and progression of replication compartments 15 1.4.2 Recruitment of viral and host factors 16 1.5 EBV capsid protein and PML nuclear bodies 16 1.5.1 PML Nuclear Bodies 16 1.5.2 Composition and Nuclear Assembly of EBV Capsid Proteins 18 1.5.3 Functional Interplay Between PML Nuclear Bodies and EBV Capsid Assembly 19 1.6 Specific aims 20 Chapter 2: Materials and methods 22 2.1 Cell culture 22 2.2 Cell transfection 23 2.3 Immunofluorescence assay (IFA) and confocal analysis 24 2.4 Immunoblotting (IB/WB) and antibodies 26 2.5 Co-immunoprecipitation assay 28 2.6 Lentivirus production 29 2.7 shRNA lentivirus transduction 30 2.8 Extraction of intracellular EBV DNA 30 2.9 Extraction of extracellular EBV virion DNA 32 2.10 Quantitative real-time PCR (qPCR) 32 2.11 Subcellular fractionation of viral DNA and proteins 33 Chapter 3: Results 35 3.1 DNAJB6a interacts with BSLF1 and promotes its nuclear translocation 35 3.2 DNAJB6a is required for efficient nuclear localization of BSLF1 in the presence of helicase-primase complex components 37 3.3 DNAJB6a does not affect the subcellular distribution of the early proteins BBLF2/3 and BBLF4 or the late protein VCA 40 3.4 HSP70 interaction is important for DNAJB6a-mediated nuclear translocation of BSLF1 41 3.5 Knockdown of DNAJB6a attenuates EBV DNA replication and virion release in TW01-EBV after Rta induction 43 3.6 Knockdown of DNAJB6a causes nuclear accumulation of EBV DNA 45 3.7 The NLS-containing minor capsid protein BORF1 localizes to PML nuclear bodies, and endogenous DNAJB6 redistributes to BORF1-associated puncta within the nucleus 46 3.8 DNAJB6 interacts with BORF1 and are associated with HSPA1A in co-immunoprecipitaion 48 3.9 Knockdown of DNAJB6a reduces the colocalization of BORF1 with PML nuclear bodies 49 3.10 BORF1 protein expression is reduced in DNAJB6a knockdown cells 52 3.11 DNAJB6a enhances BORF1 protein levels in an HSP70 interaction-dependent manner 53 3.12 BORF1 protein levels are differentially regulated by wild-type and H31Q-mutant DNAJB6 isoforms 54 3.13 Expression of DNAJB6a or its H31Q mutant alters the number and size of BORF1 nuclear puncta 55 3.14 Knockdown of DNAJB6a reduces the protein stability of BORF1 57 3.15 RNF4-mediated SUMO-targeted degradation is not responsible for reduced BORF1 levels in DNAJB6a-depleted cells 58 3.16 Endogenous DNAJB6 colocalizes with FG-Nucleoporin in the perinuclear region 61 3.17 BGLF4 does not affect the nuclear targeting of BSLF1 but alters its intranuclear distribution 62 3.18 BGLF4 reduces the interaction between BSLF1 and DNAJB6a or DNAJB6b 64 Chapter 4: Discussion 67 4.1 DNAJB6a facilitates BSLF1 nuclear import during early EBV lytic phase 67 4.2 DNAJB6a safeguards capsid assembly at PML nuclear bodies in late infection 71 4.3 Host chaperones in viral infection 76 Figures and supplements 82 Fig. 1. BSLF1-myc is co-immunoprecipitated with HA-DNAJB6a and HA-DNAJB6b. 83 Fig. 2. Both HA-DNAJB6a and HA-DNAJB6b colocalizes with BSLF1-myc and alters its subcellular distribution in HeLa cells. 84 Fig. 3. Nuclear localization of DNAJB6a is required for directing BSLF1-myc into the nucleus in HeLa cells. 86 Fig. 4. GFP-BSLF1 localizes to the nucleus when co-expressed with HA-BBLF2/3 and Myc-BBLF4 in HeLa cells. 87 Fig. 5. DNAJB6a is required for efficient nuclear localization of GFP-BSLF1 in the presence of HA-BBLF2/3. 89 Fig. 6. Expression of HA-DNAJB6a or HA-DNAJB6b does not change the subcellular localization of Myc-BBLF2/3 or Myc-BBLF4 in HeLa cells. 91 Fig. 7. HA-DNAJB6a or HA-DNAJB6b does not change the subcellular localization of HA-VCA in HeLa cells. 92 Fig. 8. The nuclear import of BSLF1-myc is facilitated by the co-expression of V5-DNAJB6a but less efficiently by the HSP70-interaction-deficient mutant V5-DNAJB6a-H31Q. 93 Fig. 9. HSPA1A, but not HSPA8, colocalizes with GFP-BSLF1 in cells expressing V5-DNAJB6 or V5-DNAJB6a-H31Q. 95 Fig. 10. Expression kinetics of viral proteins and DNAJB6a/b following Rta transfection in TW01-EBV cells. 96 Fig. 11. Knockdown DNAJB6a reduces EBV DNA replication and virion release at 48 hours post-Rta transfection of TW01-EBV cells. 98 Fig. 12. DNAJB6a knockdown-mediated reduction of virion release is associated with nuclear retention of EBV DNA in TW01-EBV, at 48 or 72 h post-Rta transfection. 100 Fig. 13. EGFP-BORF1 colocalizes with PML and recruits DNAJB6 in HK1 cells. 101 Fig. 14. V5-DNAJB6a and V5-DNAJB6b are co-immunoprecipitated with HA-BORF1 and are associated with HSPA1A. 102 Fig. 15. DNAJB6a knockdown impairs BORF1 colocalization with PML-NBs in HK1 cells. 105 Fig. 16. HA-BORF1 expression is reduced in DNAJB6a-knockdown HK1 and 293T cells. 107 Fig. 17. HA-BORF1 expression is partially rescued by overexpression of V5-DNAJB6a wild-type, but not by the V5-DNAJB6a-H31Q in DNAJB6a-knockdown 293T cells. 108 Fig. 18. HA-BORF1 expression is differentially affected by wild-type and H31Q mutant forms of V5-DNAJB6a and V5-DNAJB6b. 109 Fig. 19. Expression of V5-DNAJB6a or its H31Q mutant alters the number and size of GFP-BORF1 nuclear puncta in HeLa cells. 111 Fig. 20. Knockdown of DNAJB6a reduces the protein stability of HA-BORF1. 113 Fig. 21. Reduction of HA-BORF1 expression in DNAJB6a-knockdown HK1 cells is not mediated by RNF4-dependent degradation of SUMOylated proteins. 114 Fig. 22. Endogenous DNAJB6 colocalizes with FG-Nucleoporin in the perinuclear region. 115 Fig. 23. EGFP-BGLF4 causes FG-Nucleoporin redistribution. 116 Fig. 24. BGLF4 does not affect the nuclear targeting of BSLF1-myc but alters its intranuclear distribution. 118 Fig. 25. BGLF4 attenuates the interaction between BSLF1-myc and HA-DNAJB6a or HA-DNAJB6b in co-immunoprecipitation. 119 Fig. 26. Hypothetical model of how DNAJB6a regulates the nuclear targeting of primase BSLF1 and capsid assembly during Epstein-Barr virus lytic replication. 120 Fig. S1. Schematic model of HSP40-HSP70-HSP90 chaperone machinery in protein folding and quality control 121 Fig. S2. The genomic structure and domain architecture of DNAJB6 (MRJ) isoforms. 122 Table 123 Table 1. Plasmid DNA 123 References 126 | - |
| dc.language.iso | en | - |
| dc.subject | EB病毒 | zh_TW |
| dc.subject | DNAJB6 | zh_TW |
| dc.subject | BSLF1 | zh_TW |
| dc.subject | 核衣殼 | zh_TW |
| dc.subject | PML核小體 | zh_TW |
| dc.subject | nucleocapsid | en |
| dc.subject | Epstein-Barr virus | en |
| dc.subject | DNAJB6 | en |
| dc.subject | BSLF1 | en |
| dc.subject | PML nuclear bodies | en |
| dc.title | DNAJB6a調控EB病毒溶裂期中引子酶BSLF1核定位與病毒衣殼組裝之機制探討 | zh_TW |
| dc.title | DNAJB6a Regulates Nuclear Targeting of Primase BSLF1 and Capsid Assembly During EBV Lytic Replication | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 鄧述諄;張麗冠;蔡明翰 | zh_TW |
| dc.contributor.oralexamcommittee | Shu-Chun Teng;Li-Kwan Chang;Ming-Han Tsai | en |
| dc.subject.keyword | EB病毒,DNAJB6,BSLF1,核衣殼,PML核小體, | zh_TW |
| dc.subject.keyword | Epstein-Barr virus,DNAJB6,BSLF1,nucleocapsid,PML nuclear bodies, | en |
| dc.relation.page | 147 | - |
| dc.identifier.doi | 10.6342/NTU202502921 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-30 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 微生物學研究所 | - |
| dc.date.embargo-lift | 2030-07-29 | - |
| 顯示於系所單位： | 微生物學科所 | |
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