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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Shu-Ching Hsu | en |
| dc.contributor.author | 許舒晴 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:30:30Z | - |
| dc.date.copyright | 2022-10-05 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84879 | - |
| dc.description.abstract | 第七型類鐸受體(TLR7)及第九型類鐸受體(TLR9)是兩個表現於漿細胞樣樹突細胞(plasmacytoid dendritic cells)的胞內體(endosome)類鐸受體，他們會辨識核酸產生大量的第一型干擾素(type I interferons)來抵禦病毒。然而過多的第一型干擾素可能會造成問題如自體免疫疾病，因此第一型干擾素的產生需要嚴密調控。我們實驗室過去發現一個E3泛素接合酶(E3 ubiquitin ligase) ──ZNRF1會透過促進caveolin-1的泛素化(ubiquitination)及降解(degradation)來正向調控第四型類鐸受體(TLR4)訊息傳遞路徑。然而，在第三型類鐸受體(TLR3)介導的免疫反應中，ZNRF1作為一個負向調控者會對第三型類鐸受體進行泛素化並造成其走向溶酶体式(lysosomal)降解。本篇研究我們發現在R848(第七型類鐸受體的配體)及CpG A(第九型類鐸受體的配體)的刺激下，類FMS酪氨酸激酶-3受體所分化的漿細胞樣樹突細胞(Flt3L-pDCs)或人類漿細胞樣樹突細胞(CAL-1)在ZNRF1缺失的情況下會增加第一型干擾素的表現，而ZNRF1的E3泛素接合酶活性對於其負向調控第七型類鐸受體誘發的第一型干擾素產生是重要的。類似於TLR3，ZNRF1會與TLR7及TLR9互動。ZNRF1會促進在第九型類鐸受體的離胺酸(lysine)932位點(residue)進行的離胺酸63型多泛素化 (K63-linked polyubiquitination)，而這樣的調控是需要其E3泛素接合酶活性。我們更進一步發現ZNRF1缺失的老化老鼠有脾臟腫大、動脈周圍淋巴鞘(periarteriolar lymphoid sheath)擴大及自體抗體增加的現象。去除第七型類鐸受體或骨髓分化因子八八蛋白質(MyD88)後減緩這些表現型(phenotype)，意味著ZNRF1有潛力扮演預防第七型類鐸受體所致自體免疫的角色。總結來說，我們認為ZNRF1負向調控第七及第九型類鐸受體訊息傳遞，並藉由降低過量第一型干擾素的產生以減緩自體免疫疾病的發展。 | zh_TW |
| dc.description.abstract | Toll-like receptor (TLR) 7 and TLR9 are two of the endosomal TLRs that expressed in plasmacytoid dendritic cells (pDCs). They sense nucleic acids and produce indispensable amounts of type I interferons (IFNs) for anti-viral response. However, excessive type I IFNs may lead to several disadvantages such as the autoimmunity, therefore type I IFNs production needs to be tightly regulated. Our lab previously found that one of the E3 ubiquitin ligases — Zinc and RING finger 1 (ZNRF1) positively regulates TLR4 signaling pathway through promoting caveolin-1 ubiquitination and degradation. However, in TLR3-mediated immune response, ZNRF1 serves as a negative regulator by ubiquitinating TLR3 for lysosomal degradation. In this study, we discovered that deletion of ZNRF1 in primary mouse fms-like tyrosine kinase 3 ligand (Flt3L)-driven pDCs or human pDCs, CAL-1, enhances type I IFNs mRNA expression after stimulation of R848 (TLR7 ligand) and CpG A (TLR9 ligand). Besides, ZNRF1 E3 ubiquitin ligase activity is required for its negative regulation of TLR7-driven type I IFN production. Similar to TLR3, ZNRF1 interacts with TLR7 and TLR9, and promotes K63-linked polyubiquitination on TLR9 lysine 932 residue in an E3 ubiquitin ligase activity-dependent manner. We further discovered that aged Znrf1-/- mice showed splenomegaly, enlarged periarteriolar lymphoid sheath and increased autoantibodies production. Depletion of TLR7 or MyD88 in Znrf1-/- mice attenuates these phenotypes, implying that ZNRF1 plays a potential role in preventing TLR7-dependent autoimmunity. Together, our data suggest that ZNRF1 negatively regulates TLR7/9 signaling, thereby decreasing the excessive production of type I IFNs and preventing the development of autoimmunity. | en |
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| dc.description.tableofcontents | 口試委員會審定書......ii 致謝......iii 摘要......iv Abstract......v Contents......vii Introduction......1 Pattern-recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs)......1 TLRs......2 Nucleic acid-sensing TLRs......5 TLR7/9 trafficking and processing......6 TLR7/9 and their ligands......7 TLR7/9 signaling......9 pDC and type I IFNs......11 Type I IFNs and autoimmunity......12 Ubiquitination......13 Zinc and RING finger 1 (ZNRF1) and ZNRF family......14 ZNRF1 and immunity......15 Aim......17 Materials and Methods......18 Reagents and antibodies......18 Mice......22 Generation of FMS-like tyrosine kinase 3 ligand (Flt3L) driven bone marrow-derived dendritic cells (BMDCs) or pDCs......24 Cell culture and stimulation......25 Generation of ZNRF1-knockout CAL-1 cells by CRISPR-Cas9 system......26 Verification of ZNRF1 knockout in CAL-1 cells......27 Reconstitution of ZNRF1 wild-type and C184A mutants in ZNRF1 knockout CAL-1 cells......29 Construction of TLR7(K953R)-AcGFP and TLR9(K932R)-AcGFP plasmids......29 RNA extraction and Real-Time Quantitative PCR (RT-qPCR)......30 Preparation of cell lysates......33 Subcellular fractionation......33 Immunoprecipitation/Ubiquitination assay......34 Immunoblotting......35 Serological tests for autoantibodies......36 Histology......36 Statistical analysis......37 Results......38 ZNRF1 depletion in Flt3L-pDCs enhances the mRNA expression of type I IFNs after R848 and CpG A stimulation......39 ZNRF1 depletion in Flt3L-BMDCs enhances the signaling pathway involved in type I IFNs production upon R848 treatment......39 ZNRF1 depletion enhances type I IFN signaling pathway after TLR7 activation in human CAL-1 cells......41 E3 ubiquitin ligase activity of ZNRF1 is required for modulating type I IFN signaling after R848 stimulation......42 ZNRF1 interacts with TLR7 and TLR9......43 TLR9 ubiquitination is influenced by K932R mutation, and K63-linked ubiquitination is specifically mediated by enzymatic function of ZNRF1......44 ZNRF1-deficient mice develop more severe autoimmune-related symptoms, which can be reversed by deletion of TLR7 and MyD88......45 Discussion......49 The role of ZNRF1 in TLR7 mediated type I IFN expression......50 The role of ZNRF1 in TLR7/TLR9-mediated proinflammatory cytokine production......51 The expression of TLR7-AcGFP in HEK 293T cells......53 The ubiquitination of TLR9 in HEK293T......53 The contribution of ZNRF1 in autoimmunity......54 The involvement of B cells in TLR7/9-mediated autoimmunity......54 The roles of TLR7 and TLR9 in autoimmunity......55 Figures......57 Figure 1. ZNRF1 depletion in mice does not influence Flt3L-induced BMDCs and pDCs differentiation......57 Figure 2. Deletion of ZNRF1 enhances type I IFN mRNA expression after R848 and CpG A stimulation in Flt3L-pDCs......59 Figure 3. ZNRF1 depletion in Flt3L-BMDCs enhances signaling involved in type I IFN production upon R848 treatment......60 Figure 4. ZNRF1 depletion in CAL-1 cells enhances type I IFN mRNA expression upon R848 treatment......61 Figure 5. ZNRF1 depletion in CAL-1 cells increases signaling involved in type I IFN production upon R848 treatment......62 Figure 6. ZNRF1 depletion upregulates IRF7 nuclear translocation in CAL-1 cells after R848 stimulation......63 Figure 7. The E3 ubiquitin ligase activity of ZNRF1 is essential for regulating type I IFN expression upon R848 treatment......64 Figure 8. ZNRF1 interacts with TLR7 and TLR9......65 Figure 9. ZNRF1 catalyzes TLR9 K63-linked ubiquitination at K932......67 Figure 10. Depletion of TLR7 under Znrf1-/- background does not cause any developmental abnormality......70 Figure 11. Aged Znrf1-/- mice generate slightly more anti-SmRNP and anti-dsDNA autoantibodies in a TLR7-MyD88 dependent manner......71 Figure 12. ZNRF1-deficient mice show enlarged white pulps in the spleen, which is reversed by deletion of TLR7 or MyD88......72 Figure S1. ZNRF1 expression is induced by TLR7/9 ligands......73 Figure S2. Deletion of ZNRF1 in mice develops autoimmune-like symptoms......74 References......75 | |
| dc.language.iso | en | |
| dc.subject | 自體免疫 | zh_TW |
| dc.subject | 第一型鋅暨環指泛素連接酶 | zh_TW |
| dc.subject | 第七型類鐸受體 | zh_TW |
| dc.subject | 第九型類鐸受體 | zh_TW |
| dc.subject | 漿細胞樣樹突細胞 | zh_TW |
| dc.subject | 第一型干擾素 | zh_TW |
| dc.subject | Toll-like receptor 7 | en |
| dc.subject | autoimmunity | en |
| dc.subject | type Ι interferon | en |
| dc.subject | plasmacytoid dendritic cell | en |
| dc.subject | Toll-like receptor 9 | en |
| dc.subject | Zinc and ring finger 1 | en |
| dc.title | ZNRF1調控第七/九型類鐸受體誘發的發炎反應之功能 | zh_TW |
| dc.title | The regulatory function of ZNRF1 in TLR7/9-driven inflammatory responses | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李建國(Chien-Kuo Lee),呂春敏(Chuen-Miin Leu) | |
| dc.subject.keyword | 第一型鋅暨環指泛素連接酶,第七型類鐸受體,第九型類鐸受體,漿細胞樣樹突細胞,第一型干擾素,自體免疫, | zh_TW |
| dc.subject.keyword | Zinc and ring finger 1,Toll-like receptor 7,Toll-like receptor 9,plasmacytoid dendritic cell,type Ι interferon,autoimmunity, | en |
| dc.relation.page | 87 | |
| dc.identifier.doi | 10.6342/NTU202202844 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-08-29 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2027-08-26 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
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