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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
dc.contributor.author | Yu-Hsuan Chen | en |
dc.contributor.author | 陳鈺軒 | zh_TW |
dc.date.accessioned | 2021-06-16T13:02:50Z | - |
dc.date.available | 2025-06-23 | |
dc.date.copyright | 2020-07-01 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-06-28 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61428 | - |
dc.description.abstract | 泛素-蛋白酶體系統和細胞自噬是兩個主要的細胞品管路徑,它們的功能紊亂皆牽連著各式各樣的疾病。然而,此兩路徑的交互影響仍然未被透徹了解。在本篇研究中,我們發現泛素連接酶UBE3C和去泛素化酶TRABID相互拮抗調控VPS34的K29/K48分支型泛素化,從而平衡地維持基本與營養缺失誘導的細胞自噬活性。我們研究指出此泛素化增強了VPS34與蛋白酶體的結合與它的降解,由此抑制自噬小體的生成與成熟。在內質網和蛋白毒性壓力的情況下,位在吞噬泡的UBE3C蛋白量會下降,同時與蛋白酶體結合的UBE3C的蛋白量會上升,營養缺失的條件下則沒有觀察到此現象。此UBE3C位置與蛋白交互作用的改變,減少UBE3C對VPS34的負向調控,從而增加包括蛋白質聚合體自噬與內質網自噬的細胞自噬活性來促進蛋白質恆定、內質網品管和細胞存活。在肝臟,TRABID促使的VPS34蛋白穩定路徑對脂質代謝是非常重要的,脂肪變性病程中會負向調節此分子機制。綜觀來說,本研究證實VPS34的新穎泛素化型態以及闡明此VPS34修飾對細胞蛋白質恆定和生理上的肝臟代謝有重要功能。 | zh_TW |
dc.description.abstract | Ubiquitin-proteasome system (UPS) and autophagy are two major quality control processes whose impairment is linked to a wide variety of diseases. However, the interplay between UPS and autophagy remains incompletely understood. Here, we show that ubiquitin ligase UBE3C and deubiquitinating enzyme TRABID reciprocally regulate K29/K48 branched ubiquitination of VPS34 to balance basal and nutrient starvation-induced autophagy. This ubiquitination enhances the binding of VPS34 to proteasome for degradation, thereby suppressing autophagosome formation and maturation. Under ER and proteotoxic stresses, but not nutrient starvation UBE3C recruitment to phagophore is compromised with a concomitant increase of its association with proteasomes. This switch attenuates the action of UBE3C on VPS34, thereby elevating autophagy activities including aggrephagy and ER-phagy to facilitate proteostasis, ER quality control and cell survival. In the liver, TRABID-mediated VPS34 stabilization is critical for lipid metabolism and is downregulated during the pathogenesis of steatosis. This study identifies a previously unappreciated ubiquitination type on VPS34 and elucidates its cellular fate and physiological functions in proteostasis and liver metabolism. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T13:02:50Z (GMT). No. of bitstreams: 1 U0001-2806202000511300.pdf: 7390542 bytes, checksum: 39ebd03b321d22065efd6c27314f8b2a (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | Contents 謝辭 ii 摘要 iv Abstract v Contents vi List of Figures x List of Appendixes xv List of Tables xvi I. Introduction 1 1. Autophagy 1 1-1 Autophagic process overview 1 1-2 A lifecycle of the autophagosome 2 1-3 Molecular mechanisms 4 1-4 Selective autophagy 10 1-4-1 The molecular mechanism of aggrephagy 11 1-4-2 The molecular mechanism of ER-phagy 13 1-5 The physiological and pathological functions of autophagy 14 2. VPS34 complexes 16 2-1 Compositions and architectures of VPS34 complexes 16 2-2 Cellular and physiological function 21 2-3 Post-translational modification of the VPS34 complex for autophagy regulation 25 3. Ubiquitination 29 3-1 Ubiquitination machinery 29 3-2 The complexity of protein ubiquitination 30 3-3 Ubiquitin E3 ligases 32 3-4 UBE3C 33 3-5 Deubiquitinases (DUBs) 36 3-6 TRABID 38 4. Ubiquitin signal in autophagy regulation 41 4-1 Crosstalk between ubiquitin proteasome system and autophagy 41 4-2 Ubiquitin-mediated degradation in autophagy regulation 46 4-3 Non-proteolytic ubiquitination in autophagy regulation 49 4-4 Deubiquitinases in autophagy regulation 50 II. Material and Methods 54 Plasmids 54 Antibodies and reagents 55 Cell culture and transfection 55 Lentivirus production and infection 56 RNA interference 57 Generation of CRISPR KO cell line 57 Western blot 58 Immunoprecipitation 58 Immunofluorescence 59 Confocal microscopy and image analysis 60 shRNA screening and high-throughput image analysis 60 In vitro binding 61 In vivo ubiquitination and deubiquitination assays 62 In vitro ubiquitination and deubiquitination assays 62 Diubiquitin cleavage assay 63 Lbpro* purification and treatment 64 LC-MS/MS and label-free quantification 65 Chemical-induced dimerization 67 Protein aggregate clearance assay 67 Apoptosis assay 68 Mouse Model of Non-Alcoholic Fatty Liver Disease and Mouse Experiments 69 Histology 70 Immunofluorescence staining of paraffin-embedded tissues 70 Oil Red O staining 71 Serum biochemical analysis 71 Protein Extraction from Liver 72 Hepatic triglyceride level 72 Statistical Analysis 73 III. Results 74 TRABID positively regulates autophagosome formation 74 TRABID impacts on the VPS34/class III PI3-kinase during autophagosome formation 75 TRABID associates with VPS34 complex I and II and promotes autophagosome-lysosome fusion 75 TRABID reduced VPS34 Lys29/48-linked heterotypic ubiquitination to stabilize VPS34 77 UBE3C is a physiological and direct binding partner of VPS34 80 UBE3C potentiates VPS34 ubiquitination and proteolysis to inhibit autophagy 80 UBE3C assembles the K29/K48 branched ubiquitin chains on VPS34 81 VPS34 K29/K48 branched ubiquitination enhances its proteasome binding and degradation 83 UBE3C and TRABID coordinately govern a balanced autophagy activity 84 ER and proteotoxic stresses attenuate UBE3C’s action on VPS34 and enhances its proteasome association 85 Enforced targeting of UBE3C to VPS34 attenuates both ER and proteotoxic stresses-induced autophagy 87 Enforced the UBE3C recruitment to VPS34 compromises ER and protein quality control during ER-phagy and aggrephagy 89 Dysregulation of TRABID/VPS34 axis contributes to liver steatosis 90 IV. Discussion 93 V. References 99 VI. Figures 130 VII. Appendixes 216 VIII. Tables 227 | |
dc.language.iso | en | |
dc.title | UBE3C與TRABID拮抗調控VPS34的K29/K48分支型泛素化,藉此調控細胞自噬、蛋白質恆定與肝臟代謝 | zh_TW |
dc.title | VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳光超(Guang-Chao Chen),楊維元(Wei Yuan Yang),蔡亭芬(Ting-Fen Tsai),姜為中(Wei-Chung Chiang) | |
dc.subject.keyword | NULL | en |
dc.relation.page | 236 | |
dc.identifier.doi | 10.6342/NTU202001165 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-06-29 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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