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研究生： 陳奐達
Chen, Huan-Da
論文名稱： 線蟲轉錄因子HLH-30調控之自噬作用參與對抗細菌穿孔毒素蛋白之防禦
HLH-30/TFEB-mediated autophagy is required for bacterial pore-forming toxin defense in Caenorhabditis elegans
指導教授： 陳昌熙
Chen, Chang-Shi
學位類別： 博士
Doctor
系所名稱： 醫學院 - 基礎醫學研究所
Institute of Basic Medical Sciences
論文出版年： 2017
畢業學年度： 105
語文別： 英文
論文頁數： 118
中文關鍵詞： 自噬作用 、秀麗隱桿線蟲 、轉錄因子HLH-30 、膜穿孔毒素蛋白(Pore-forming toxin, PFT)
外文關鍵詞： autophagy, Caenorhabditiselegans, transcription factor HLH-30/TFEB, pore-forming toxin (PFT)
相關次數： 點閱：208  下載：9 
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    • 自噬作用(Autophagy)是一個在許多物種間具有高度保守性之細胞內降解路徑，它的功能主要是在維持細胞內物質間的穩定平衡，藉由自噬小體(autophagosome)包覆細胞內失能的蛋白、受損的胞器，再與溶體(lysosome)融合後成為自噬溶小體(autolysosome)，利用溶體內多樣性的降解酵素進行物質降解以及回收再利用，並且現今的研究也指出自噬作用與胚胎的發育、細胞的分化、癌症、神經性退化疾病以及病原菌或病毒感染方面皆扮演重要的角色。秀麗隱桿線蟲 (Caenorhabditis elegans)內的轉錄因子HLH-30相對於人類的同源蛋白為TFEB，HLH-30於目前的研究指出參與許多生物體內的機能，例如調控溶體的生合成與代謝，或經由調控自噬作用進而影響壽命等，並且在最近也被報導能夠調控自噬作用而改變宿主對病原菌的感受性，但在細菌感染的研究方面卻鮮少有提到細菌的毒性因子是否能夠影響轉錄因子HLH-30的活化進而改變宿主體內自噬作用的反應。本研究中發現，餵食秀麗隱桿線蟲表現膜穿孔毒素蛋白(Pore-forming toxin)的細菌，會經由調控轉錄因子HLH-30而刺激自噬作用的大量活化。另外，在膜穿孔毒素蛋白主要作用的位置為秀麗隱桿線蟲的腸道細胞。在腸細胞內，被大量刺激的自噬作用能夠利用降解攝入的膜穿孔毒素蛋白的機制，以及影響由膜穿孔毒素蛋白造成的受損細胞膜修補的機制，來幫助宿主抵禦由膜穿孔毒素蛋白的傷害。本研究的結果證實，在受到膜穿孔毒素蛋白的攻擊時，轉錄因子HLH-30會在轉錄層面調控自噬作用的活化，並且在保護宿主抵禦膜穿孔毒素蛋白是必須的角色。總結來說，本研究提供了當宿主受到細菌的膜穿孔毒素蛋白刺激下，HLH-30與自噬作用密切的上下游調控關係以及自噬作用參與在宿主上皮細胞抵禦膜穿孔毒素蛋白的機制。

    Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components through the autophagosomal-lysosomal pathway. Nowadays research indicates autophagy plays important roles in various mechanisms such as embryogenesis and cell differentiation, cancer, degenerative neuron diseases, bacterial and viral infection. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate lysosomal biogenesis and aging through autophagy. Furthermore, HLH-30 is also involved in modulating the tolerance to bacterial infection through autophagy, but less is known about the bona fide bacterial virulent factor that activates HLH-30 and autophagy. Here, we unveil that bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and contributes to the repair of membrane-pore autonomously in the PFT-targeted intestinal cells in C. elegans. These results demonstrate that autophagy is induced partly at the transcriptional level through HLH-30 activation and is required to protect metazoan upon PFT intoxication. Together, our data show a new insight between HLH-30-mediated autophagy and epithelium intrinsic cellular defense against the single most common mode of bacterialvirulent factor attack in vivo.

    致謝 I 中文摘要 II ABSTRACT IV INTRODUCTION Pore-forming toxins 1 Autophagy 3 HLH-30 6 Caenorhabditis elegans 8 ABBREVIATIONS AND ACRONYMS 11 MATERIALS AND METHODS C. elegans and bacteria strains 13 Media and chemicals 14 Quantitative Cry PFTs susceptibility 15 RNA interference (RNAi) 15 C. elegans autophagy analysis and microscopy 16 Real-time RT-PCR 18 In silico transcription factor prediction 18 Transcriptomic analysis of the hlh-30-dependent Cry5B response genes 19 Data analysis 20 RESULTS Pore-forming toxin Cry5B activates autophagy in intestine of C. elegans 21 Autopahgy is required for the defense of C. elegans against Cry5B 25 Autophagy functions cell-autonomously in the intestine to protect against Cry5B 28 Autophagy is involved in xenophagic degradation of PFT and contributed to damaged membrane-pore repair 30 Transcription factor HLH-30 regulates the expression of Cry5B-activated atg genes 33 HLH-30-mediated autophagy is required for other PFT defense in C. elegans 35 HLH-30 regulates the transcription of other membrane-repair related genes in response to Cry5B intoxication 37 CONCLUSION 40 REFFERENCES 45 FIGURES Fig. 1 Cry5B activates autophagy related genes at transcriptional level 57 Fig. 2 Cry5B induces LGG-1 activation at translational and post translational modification level 58 Fig. 3 Cry5B induces GFP::LGG-1 signal in intestine 59 Fig. 4 Cry5B activates autophagic flux 61 Fig. 5 The Cry5B-activated atg genes are required for autophagy induction 62 Fig. 6 The response of GFP::LGG-1 puncta in intestine is specific to Cry5B 63 Fig. 7 Cry5B induces intestine morphology disordered and autophagosomal vesicle formation in C. elegans 64 Fig. 8 Autophagy related mutants are hypersensitive to Cry5B 65 Fig. 9 C. elegans with RNAi knockdown Cry5B-activated atg genes are hypersensitive to Cry5B toxicity 66 Fig. 10 C. elegans overexpressing lgg-1 gene is resistant to Cry5B 67 Fig. 11 Spermidine induces autophagy against Cry5B intoxication 68 Fig. 12 Cry5B-activated atg genes are essential for survival and cellular autophagy activation 69 Fig. 13 C. elegans with RNAi knockdown Cry5B-activated atg genes in intestine are hypersensitive to Cry5B 70 Fig. 14 atg-18 intestinal complement animals are resistant to Cry5B compared to atg-18 mutant animal 71 Fig. 15 C. elegans overexpressing lgg-1 gene in intestine is resistant to Cry5B 73 Fig. 16 Rh-Cry5B and GFP::LGG-1 multiple cellular puncta in intestine depend on pore formation 74 Fig. 17 Autophagy plays a role in Cry5B degradation 75 Fig. 18 Autophagy contributes to membrane pore-repair 76 Fig. 19 Transcription factor HLH-26 and HLH-30 recognized promoter consensus motif of Cry5B-activated atg genes 77 Fig. 20 Cry5B-induced autophagy depends on HLH-30 78 Fig. 21 hlh-30 mutant is hypersensitive to Cry5B 80 Fig. 22 HLH-30 regulates Cry5B-activated atg genes expression 81 Fig. 23 Cry5B induces HLH-30 nuclear translocation 82 Fig. 24 HLH-30 mediates autophagy against Cry5B intoxication 83 Fig. 25 HLH-30 contributes to membrane pore-repair 84 Fig. 26 Cry21A induces GFP::LGG-1 signal in intestine 85 Fig. 27 Autophagy is required for Cry21A defense 86 Fig. 28 Cry21A regulates HLH-30 nuclear translocation 87 Fig. 29 hlh-30 is required for Cry21A defense 88 Fig. 30 Autophagy is required for streptolysin O (SLO) defense in C. elegans 89 Fig. 31 The Venn diagram of thehlh-30-dependent Cry5B response genes 90 Fig. 32 The DAVID analysis of the hlh-30-dependent Cry5B response genes 91 Fig. 33 hlh-30-dependent Cry5B response genes contribute to membrane pore-repair 92 Fig. 34 HLH-30 nuclear translocation is independent of Cry5B defense signal pathways 93 Fig. 35 Schematic illustrating relationship between HLH-30-mediated autophagy and epithelium intrinsic cellular defense (INCED) against PFT 94 TABLES Table 1. The list of hlh-30-dependent Cry5B response genes. 95 Table 2. The DAVID GO categories which might be involved in intrinsic membrane-pore repair and defense response 111 Curriculum vitae 113

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