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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89757完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳光超 | zh_TW |
| dc.contributor.advisor | Guang-Chao Chen | en |
| dc.contributor.author | 林于傑 | zh_TW |
| dc.contributor.author | Yuchieh Jay Lin | en |
| dc.date.accessioned | 2023-09-20T16:15:04Z | - |
| dc.date.available | 2025-08-08 | - |
| dc.date.copyright | 2023-09-20 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-08 | - |
| dc.identifier.citation | Aguilera, M.O.; Berón, W.; Colombo, M.I. (2012). The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy. Autophagy, 8, 1590–1603.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89757 | - |
| dc.description.abstract | 蛋白質恆定對細胞健康至關重要，是由泛素-蛋白酶體系統（UPS）和細胞自噬維持。自噬是一種具演化保留性的過程，藉由與溶酶體融合，降解包覆其中的不正常折疊蛋白或受損胞器。近年來，越來越多的研究顯示，衰老與自噬、溶酶體功能下降相關。然而，詳細的機制和有效的療法仍然不明。本研究發現去泛素化酵素dUSP45/USP45的新功能，它在果蠅和哺乳動物系統中調節自噬和溶酶體活性。我們的發現USP45使得溶酶體上的液胞型ATP酶水平下降，從而降低了溶酶體的酸化程度。與過去關於USP45潛在相互作用蛋白的質譜分析報告一致，我們的免疫沉澱結果顯示，Coronin1B（Coro1B）與USP45相互作用。此外，USP45介導了Coro1B的去泛素化，並維持其蛋白穩定性。Coro1B已知是肌動蛋白之調節蛋白，因此我們在USP45剔除的細胞中發現了共定位的溶酶體與肌動蛋白斑塊結構。進一步我們的數據也顯示，肌動蛋白聚合抑制劑Latrunculin A（LatA）和CK666會破壞液胞型ATP酶和溶酶體的共定位，進一步支持肌動蛋白在自噬調控中的作用。而Latrunculin A（LatA）沖刷實驗證明，通過置換正常培養基，可以顯著恢復USP45敲除細胞中的溶酶體活性以及肌動蛋白和溶酶體的共定位。有趣的是，我們發現，USP45敲除所導致的液胞型ATP酶水平升高取決於WASP，而不是WASH。如同我們的推測，Coro1B在抑制細胞自噬和溶酶體上的液胞型ATP酶含量，發揮了與USP45類似的作用。為了評估USP45的生理功能，我們進行了RT-PCR和西方墨點分析，顯示dUSP45 mRNA水平與成熟的Cathepsin蛋白含量在衰老過程中呈現負相關。此外，通過敲除dUSP45，可以顯著恢復HTT-多谷氨酰胺（polyQ）所引發的退化。我們的研究揭示了USP45在藉由肌動蛋白對自噬及溶酶體進行調節的新功能，以及其對溶酶體液胞型ATP酶水平的影響，並暗示USP45可能成為與衰老相關疾病的潛在治療目標。 | zh_TW |
| dc.description.abstract | Proteostasis is beneficial to cellular health, which is maintained by the ubiquitin-proteasome system (UPS) and autophagy. As an evolutionary conserved process, autophagy degrades engulfed material including misfolded protein or damaged organelles through fusion with lysosome. Recent years, increasing studies describing that aging is associated with function decline of autophagy/lysosome. However, the detail mechanism and efficient therapy remain to be discovered. This study identifies the novel function of deubiquitinase, dUSP45/USP45, which modulates autophagy and lysosomal activity in Drosophila and mammalian systems. Our findings reveal that USP45 attenuates V-ATPase level on lysosome, leading to reduced lysosomal acidification. Consistent with previous report which characterized potential interacting protein of USP45 in MS analysis, our immunoprecipitation results show Coronin1B (Coro1B) interacts with USP45. Additionally, USP45 mediates deubiquitination of Coro1B and maintains its protein stability. Coro1B is regarded as actin dynamics regulator protein, we thus find the actin patch-like structure colocalized with lysosome in USP45-depleted cell. Moreover, our data show that colocalization of V-ATPase and lysosome is disrupted by actin polymerization inhibitors, Latrunculin A (LatA) and CK666, further supporting the role of actin dynamics in autophagy regulation. Furthermore, Latrunculin A (LatA) washout experiments demonstrate that lysosomal activity and actin-lysosome colocalization are dramatically restored by replenishment of normal medium in USP45 knockdown cells. Intriguingly, we find that USP45 knockdown-induced elevation of V-ATPase level on lysosome is dependent on WASP, rather than WASH. As our speculation, Coro1B plays a similar role of USP45 in inhibiting autophagy flux and V-ATPase level on lysosome. To evaluate the physiological function of USP45, we conduct RT-PCR and western blot analyses, revealing a negative correlation between dUSP45 mRNA levels and mature cathepsin protein levels during aging. Furthermore, HTT-polygluatmine (polyQ)-induced degeneration are significantly recovered by knockdown dUSP45. Our study unravels the novel function of USP45 in autophagy/lysosome modulation through actin dynamics and its impact on lysosomal V-ATPase level and suggests USP45 as potential therapeutic target for age-related diseases. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-20T16:15:04Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-20T16:15:04Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract v Chapter 1: Introduction 1 1-1. Proteostasis 1 1-2. Autophagy 3 1-2-1. Overvie 3 1-2-2. Mechanism of autophagy 4 1-2-3. Lysosome 6 1-3. Ubiquitination 9 1-3-1. Overview 9 1-3-2. Deuibiquitinase 9 1-3-3. DUB in autophagy-lysosome mechanism 10 1-3-4. USP45 11 1-4. Actin dynamics and regulation 13 1-4-1. Overview 13 1-4-2. Actin polymerization and depolymerization 14 1-4-3. Actin in autophagy-lysosome 16 Chapter 2: Material & methods 18 Chapter 3: Results 26 3-1. dUSP45 is a negative regulator of autophagy 26 3-2. dUSP45 inhibits lysosome acidification by disrupting V-ATPase translocation to lysosomes 28 3-3. Mammalian USP45 negatively regulates autophagy 30 3-4. USP45 interacts with and regulates the protein stability of Coronin1B 33 3-5. USP45 knockdown promotes actin polymerization at lysosome which is required for V-ATPase localization at lysosome and acidification 34 3-6. Coro1B inhibits autophagy and lysosomal function 37 3-7. PolyQ-induced degeneration could be rescued by depleting dUSP45 39 Chapter 4: Discussion 42 References 48 Figures 57 Appendix 110 | - |
| dc.language.iso | en | - |
| dc.subject | 細胞自噬 | zh_TW |
| dc.subject | 去泛素化酵素 | zh_TW |
| dc.subject | 溶酶體 | zh_TW |
| dc.subject | 肌動蛋白動態性 | zh_TW |
| dc.subject | 液胞型ATP酶 | zh_TW |
| dc.subject | lysosome | en |
| dc.subject | USP45 | en |
| dc.subject | actin dynamics | en |
| dc.subject | autophagy | en |
| dc.subject | V-ATPase | en |
| dc.title | 去泛素化酵素USP45藉由調節肌動蛋白之動態性以調控細胞自噬及溶酶體的活性 | zh_TW |
| dc.title | Deubiquitinase USP45 regulates autophagy/lysosome activity by modulating actin dynamics | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 陳瑞華;桑自剛;姚季光;詹智強;劉雅雯 | zh_TW |
| dc.contributor.oralexamcommittee | Ruey-Hwa Chen;Tzu-Kang Sang;Chi-Kuang Yao;Chih-Chiang Chan;Ya-Wen Liu | en |
| dc.subject.keyword | 細胞自噬,溶酶體,去泛素化酵素,肌動蛋白動態性,液胞型ATP酶, | zh_TW |
| dc.subject.keyword | autophagy,lysosome,USP45,actin dynamics,V-ATPase, | en |
| dc.relation.page | 113 | - |
| dc.identifier.doi | 10.6342/NTU202303540 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-08-09 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科學研究所 | - |
| dc.date.embargo-lift | 2025-08-08 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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