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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中 | |
dc.contributor.author | Chih-Yuan Lee | en |
dc.contributor.author | 李志元 | zh_TW |
dc.date.accessioned | 2021-05-19T17:54:47Z | - |
dc.date.available | 2022-03-01 | |
dc.date.available | 2021-05-19T17:54:47Z | - |
dc.date.copyright | 2017-03-01 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-01-23 | |
dc.identifier.citation | Reference:
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7820 | - |
dc.description.abstract | 泛素接合酶(ubiquitin E3 ligase)是一種蛋白酵素,它可以辨認並催化特定蛋白與泛素(ubiquitin)進行共價鍵結。泛素鍵結作用調控了許多各種不同的重要細胞功能,包括細胞週期的控制、細胞內蛋白質運送、DNA修復、以及細胞內訊息傳導。在這篇研究裡面,主旨在研究泛素接合酶對於第四型類鐸受體(Toll-like receptor 4)訊息調控的影響。我們發現有一個泛素接合酶ZNRF1可以藉由影響另一個蛋白質caveolin-1 (CAV1)來調控第四型類鐸受體受到刺激之後產生的免疫反應。我們也發現了ZNRF1與CAV1會有接觸與作用,在細胞受到脂多糖(lipopolysaccharide)的刺激後,ZNRF1會催化CAV1接受泛素鍵結並促使CAV1在細胞內分解。CAV1在細胞內是細胞小凹(caveolae)主要的組成蛋白並調控許多細胞生理功能以及變化,例如發炎反應以及癌細胞的生長。目前已之泛素鍵結作用可以影響CAV1在細胞內表現量的變化。我們的研究同時也發現ZNRF1與CAV1在第四型類鐸受體受到活化之後,會調控Akt與GSK3b的功能來增加促進發炎反應細胞激素的分泌並且減少抑制發炎反應細胞激素的分泌。剔除ZNRF1基因的基因轉殖小鼠可以減少發炎反應並且剔除ZNRF1基因的基因轉殖小鼠對於內毒素(endotoxin)或是敗血症引起的休克有比較高的抵抗力以及存活率。我們的研究發現ZNRF1這個蛋白對於第四型類鐸受體引起的發炎反應是一個新的調控蛋白質,我們也發現了一個新的調控機制透過CAV1來影響第四型類鐸受體引起的發炎反應。 | zh_TW |
dc.description.abstract | Ubiquitination catalyzed by E3 ligases are important enzymes in cell biology and regulate diverse cellular functions such as cell cycle control, protein trafficking, DNA repair, and signaling. Many E3 ubiquitin ligases have been characterized as important immune regulators. To characterize the molecular mechanisms underlying the immunoregulatory functions of these E3 ligases in physiologically relevant immune cells is still a challenge. Our research found that E3 ubiquitin ligase ZNRF1 modulates caveolin-1 (CAV1) protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. We demonstrate that ZNRF1 interacts with CAV1 in response to lipopolysaccharides and mediates its ubiquitination and degradation. CAV1, the major constituent of caveolae, plays a pivotal role in various cellular physiological and pathological processes. The ubiquitin pathway is known to regulate the level of CAV1 in cells. Our research also found that ZNRF1-CAV1 axis regulates Akt-GSK3b activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine. Znrf1-deficient mice are more resistant to endotoxic and polymicrobial septic shock due to attenuated inflammation. Our study has identified ZNRF1 as a new regulator of TLR4-induced inflammatory responses and revealed a novel mechanism for the regulation of TLR4 signaling through CAV1. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:54:47Z (GMT). No. of bitstreams: 1 ntu-106-D97448005-1.pdf: 3339263 bytes, checksum: f0b440900a5f393985a6d4c434ca66a1 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | Introduction 9
1. Inflammation & Innate immunity 9 2. Ubiquitination 11 3. E3 ubiquitin ligase 13 (1). HECT-type E3 Ubiquitin Ligases 14 (2). RING-type E3 ligase 14 (3). PHD Domain-Containing E3 Ligases 16 (4). U-Box E3 Ligases 16 (5). RING-between-RING (RBR) E3 ubiquitin ligase 17 4. E3 Ubiquitin Ligase and Immune Response 18 5. Ubiquitination in TLR Signaling 20 6. ZNRF1 21 7. Caveolae and Inflammatory Signaling 23 Purpose of the Study 26 Material and Methods 27 Plasmids 27 Reagents and Antibodies 27 Mice 29 Cell Cultures and BMDM Preparation 29 mRNA Purification and Quantitative RT-PCR (RT-qPCR) 30 shRNA-Mediated Gene Silencing, Transfection, and Lentiviral Infection 31 siRNA Duplexes and Electroporation 32 Enzyme-Linked Immunoabsorbent Assays (ELISA) and Myeloperoxidase (MPO) Activity Assay 32 Immunoprecipitation and Immunoblotting 33 InVitro Ubiquitination Assay 34 PP2A Activity Measurement 34 In Vivo Administration of siRNAs 35 Animal Models of Endotoxemia and Polymicrobial Sepsis 35 Statistical Analysis 36 Results 37 ZNRF1 Plays an Important Role in the Regulation of the Inflammatory Response in Macrophages 37 Abrogation of ZNRF1 Mediated Signaling Protects Mice from CLP- and LPS-induced Septic Shock 39 ZNRF1 Mediates CAV1 Protein Degradation 41 ZNRF1 Regulates CAV1 Protein Stability by Polyubiquitination 43 ZNRF1 Mediates Akt-GSK3β Signalling and Regulates LPS-induced Cytokine Production 46 ZNRF1 Modulated TLR4- and CLP-triggered Inflammatory Responses through CAV1 48 Discussion 50 Table 1. 56 Complete blood counts of Znrf1Δ and Znrf1F/F mice 56 Table 2. 57 Primer pairs for RT-qPCR 57 Figure 1. Strategy for generation of Znrf1 conditional knockout mice 59 Figure 2. ZNRF1 deletion impairs the LPS-induced pro-inflammatory response. 60 Figure 3. ZNRF1 activity is required for LPS-induced cytokine production. 62 Figure 4. Znrf1∆ mice tolerating LPS-induced sepsis. 64 Figure 5. Znrf1∆ mice tolerating CLP-induced sepsis. 65 Figure 6. Serum from Znrf1∆ mice possess decreased cytokine and chemokine production after CLP. 66 Figure 7. CLP- challenged Znrf1Δ mice display limited injury in lung tissues with immunohistochemical staining. 67 Figure 8. CAV1 protein expression are increased in Znrf1Δ mice. 69 Figure 9. ZNRF1 regulates CAV1 protein levels. 70 Figure 10. CAV1 protein degradation is through proteasome degradation in Znrf1 knockdown macrophages. 71 Figure 11. E3 activity of ZNRF1 is required for CAV1 degradation. 73 Figure 12. ZNRF2 has less effect on CAV1 protein levels and TLR4-mediated inflammation. 75 Figure 13. ZNRF1 associates with CAV1 76 Figure 14. Amino acids 1-145 region of ZNRF1 interacts with CMAD domain of CAV1. 79 Figure 15. ZNRF1 targets to K39R of CAV1 and affects the inflammatory response. 80 Figure 16. AKT activation is enhanced in Znrf1 deficient and CAV1-expressing macrophages. 82 Figure 17. Akt-GSK3β-CREB signaling is altered in Znrf1 deficient and CAV1-expressing macrophages. 85 Figure 18. NFκB activation is decreased in Znrf1 deficient and CAV1-expressing macrophages. 86 Figure 19. Double deletions of Znrf1 and Cav1 in macrophages rescue the phenotype of cytokine expression. 88 Figure 20. ZNRF1-mediated TLR4- and CLP-triggered inflammatory responses depend on CAV1. 90 Figure 21. A proposed model summarizing the control of CAV1 protein level and TLR-triggered immune responses by ZNRF1. 91 Supplementary Figure 1. E3 ligase activity of ZNRF1 promotes ubiquitination of CAV1. 93 Supplementary Figure 2. ZNRF1 mediates CAV1 polyubiquitination at lysine 39. 95 Reference: 96 | |
dc.language.iso | en | |
dc.title | 泛素接合酶ZNRF1藉由影響caveolin-1之代謝影響第四型類鐸受體驅動之免疫反應 | zh_TW |
dc.title | The Ubiquitin Ligase ZNRF1 Promotes Caveolin-1 Ubiquitination and Degradation to Modulate TLR4-driven Immune Response | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林國儀,王致恬,伍安怡,李芳仁 | |
dc.subject.keyword | ZNRF1,caveolin-1,TLR4,第四型類鐸受體, | zh_TW |
dc.subject.keyword | ZNRF1,caveolin-1,TLR4, | en |
dc.relation.page | 105 | |
dc.identifier.doi | 10.6342/NTU201700165 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2017-01-23 | |
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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