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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
dc.contributor.author | Yu-Hsin Ho | en |
dc.contributor.author | 何育信 | zh_TW |
dc.date.accessioned | 2021-06-15T11:50:37Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-11 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49821 | - |
dc.description.abstract | 類鐸受體(Toll-like receptors)在先天性免疫反應中扮演著重要的角色。這類型的受體藉由辨識病原體上特定的構造(pathogen-associated molecular patterns, PAMPs)以及從壞死或受到刺激細胞所釋放出來的物質(damage-associated molecular patterns, DAMPs)達到宿主對抗外來病原體的入侵。我們先前嘗試去尋找調控第四類鐸受體(TLR4)的調控因子,並發現Znrf1基因在巨噬細胞受到第四類鐸受體的受質脂多醣(lipopolysaccharide, LPS)的刺激後會被誘發起來。ZNRF1在先前的研究中已被報導和神經細胞變性(neural degeneration)有關,然而其在先天性免疫中所扮演的角色仍是未知的。我們先前的研究結果證實ZNRF1透過調控微囊(caveolae)構造中的微囊蛋白1 (Caveolin-1)的降解,促進前發炎激素(pro-inflammatory cytokines)的製造,並抑制介白素10 (Interleukin-10, IL-10)這個抗發炎激素的產生,此顯示著ZNRF1在第四類鐸受體中扮演著正調控的角色。然而其在核內體上的類鐸受體(endosomal TLRs)所誘發的免疫反應中扮演的角色仍是未知的。因此本研究的主旨為探討其在這類型受體,特別是針對第三類鐸受體(TLR3),所調控的免疫反應中扮演的角色進行探討。我們的研究結果顯示在巨噬細胞中,若第三、第七、第九類鐸受體活化後,Znrf1基因的剔除會促進前發炎激素和第一型干擾素(type I interferons)的製造。我們更進一步尋找可能的調控機轉。我們發現在第三類鐸受體活化後,ZNRF1會透過和受體結合促使其被送往溶酶體(lysosome)降解。此外,我們也發現微囊蛋白1參與在此調控機轉中。在巨噬細胞中,Znrf1基因剔除所導致微囊蛋白1表現量的提升會去抑制溶酶體的功能。總結來說,本研究發現ZNRF1利用調控第三類鐸受體降解,負調控其所引發的免疫反應。 | zh_TW |
dc.description.abstract | Toll-like receptors (TLRs) play crucial roles in innate immune response against pathogenic infection by recognition of specific pathogen-associated molecular patterns (PAMPs) or endogenous damage-associated molecular patterns (DAMPs) released from damaged or stressed cells. We previously sought to identify regulators involved in the regulation of TLR4-mediated immune response, and found that ZNRF1, which was induced upon TLR4 activation by LPS challenge in macrophages. ZNRF1 was reported to be involved in neural degeneration, but its role in innate immune response remains unclear. Our previous studies demonstrated that ZRNF1 enhanced the production of pro-inflammatory cytokines and suppressed anti-inflammatory cytokine IL-10 expression upon LPS stimulation through controlling the protein stability of CAV1, a crucial component of caveolae. It suggests that ZNRF1 positively regulates TLR4-triggered inflammatory response. However, its role in endosomal TLRs (TLR3/7/9)-driven immune responses remains unclear. Thus in this study, we aim to characterize its function in inflammatory responses triggered by endosomal TLRs, especially focusing on TLR3. Our results show that the production of pro-inflammatory cytokines and type I interferons is significantly increased in Znrf1-depleted macrophages after activation of three endosomal TLRs. We further explore the possible regulatory mechanism and find that ZNRF1 associates with TLR3 and controls protein stability of TLR3 through the lysosome-mediated degradation after receptor activation. In addition, we demonstrate that CAV1 is involved in this regulation. Elevated CAV1 protein level caused by ZNRF1 depletion suppresses lysosomal function in macrophages upon TLR3 engagement. Taken together, this study suggests that ZRNF1 negatively regulates TLR3-mediated immune response through the control of receptor stability. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:50:37Z (GMT). No. of bitstreams: 1 ntu-105-R03448003-1.pdf: 5223843 bytes, checksum: 44dbd805b0f2deb2e50e4e31bde5a843 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員審定書 i
致謝 ii 摘要 iii Abstract iv Contents vi Introduction 1 Pattern recognition receptors (PRRs) 1 Toll-like receptors (TLRs) and their ligands 2 TLR signaling pathways 5 Negative regulators in the TLR3 signaling pathway 10 TLR3 and viruses 13 Trafficking of endosomal TLRs 14 Processing and maturation of endosomal TLRs 17 Ubiquitin and ubiquitination 18 Ubiquitination in regulation of TLR signaling 21 Zinc and RING finger 1 (ZNRF1) and other ZNRF family members 22 Specific aim 25 Materials and Methods 26 Reagents and antibodies 26 Plasmids 27 Cell culture and transfection 28 shRNA-mediated Znrf1 gene silencing and lentiviral infection 29 Mice 29 Preparation of bone marrow-derived macrophages (BMDMs) 30 Isolation of peritoneal macrophages (pMϕs) 31 Virus amplification and purification 31 Viral infection of cells 32 Plaque assay for viral titration 33 Preparation of cell lysate 33 Immunoblotting 34 Immunoprecipitation 35 Cytosolic and nuclear fractionation 35 RNA extraction and quantitative RT-PCR (RT-qPCR) 36 Luciferase reporter assay 38 Immunofluorescence 39 Flow cytometry analysis 39 Statistical analysis 40 Results 41 ZNRF1 modulates endosomal TLRs-triggered immune responses 41 ZNRF1 negatively regulates the TLR3–TRIF pathway 43 ZNRF1 regulates TLR3 protein degradation but not its proteolytic processing 44 ZNRF1 associates with and promotes poly-ubiquitination of endosomal TLRs 46 ZNRF1 promotes lysosomal degradation of TLR3 and lysosome activity 47 CAV1 mediates TLR3-driven inflammatory response 49 ZNRF1 is dispensable for the host against DENV and EMCV infection 50 ZNRF1 is not required for hematopoiesis and normal development of immune cells 52 Discussion 53 The role of ZNRF1 in modulation of endosomal TLRs-driven inflammatory responses 54 Regulation of TLR3 protein stability by ZNRF1 56 Regulation of TLR3-triggered immune response by CAV1 58 The role of ZNRF1 in anti-viral immunity 59 ZNRF1 in human diseases 61 Figures 63 Figure 1. ZNRF1 protein expression is induced in response to different TLR ligands. 63 Figure 2. ZNRF1 negatively regulates poly(I:C)-induced signaling in macrophages. 65 Figure 3. The mRNA expression of pro-inflammatory cytokines and type I IFNs is increased in ZNRF1-deficient macrophages in response to TLR3 ligand. 67 Figure 4. ZNRF1 deficiency increases activation of MAPKs and IKK/NF-κB after TLR7 engagement. 69 Figure 5. ZNRF1 deficiency promotes the production of type I IFNs and inflammatory cytokines in response to TLR7 ligand. 70 Figure 6. ZNRF1 negatively mediates TLR9-induced p38 in macrophages. 71 Figure 7. The expression of type I IFNs, but not pro-inflammatory cytokines, is enhanced in CpG-induced ZNRF1 knockdown macrophages. 72 Figure 8. ZNRF1 negatively regulates IFNβ promoter activity driven by the TLR3–TRIF pathway. 73 Figure 9. ZNRF1 does not regulate TLR3 proteolytic processing. 75 Figure 10. ZNRF1 enhances TLR3 protein degradation. 77 Figure 11. ZNRF1 associates with and mediates endosomal TLRs poly-ubiquitination. 80 Figure 12. ZNRF1-mediated TLR3 protein degradation is partially through the lysosomal degradation pathway. 81 Figure 13. Loss of ZNRF1 enhances lysosomal function in TLR3-activated macrophages. 82 Figure 14. Overexpression of CAV1 positively regulates TLR3 signaling in macrophages. 84 Figure 15. Overexpression of CAV1 in macrophages enhances cytokines and IFN-β production after TLR3 activation. 85 Figure 16. CAV1 controls TLR3 protein degradation in response to poly(I:C). 86 Figure 17. ZNRF1 deficiency does not influence DENV-induced immune response and viral clearance. 88 Figure 18. Loss of ZNRF1 does not impact the clearance of EMCV in macrophages. 90 Figure 19. ZNRF1 is not required for normal development and hematopoiesis. 91 Figure 20. The proposed model for the regulation of TLR3-induced immune response by ZNRF1. 92 References 93 | |
dc.language.iso | en | |
dc.title | E3泛素連接酶ZNRF1在TLR3誘發之免疫反應中的角色 | zh_TW |
dc.title | The Role of the E3 Ubiquitin Ligase ZNRF1 in TLR3-driven Immune Response | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 薛一蘋(Yi-Ping Hsueh),李建國(Chien-Kao Lee),劉旻禕(Min-Yi Liu) | |
dc.subject.keyword | ZNRF1,TLR3,免疫反應, | zh_TW |
dc.subject.keyword | ZNRF1,TLR3,immune response, | en |
dc.relation.page | 104 | |
dc.identifier.doi | 10.6342/NTU201602417 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-12 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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