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研究生： 蘇郁清
Su, Yu-Chin
論文名稱： 神經壞死病毒所誘發宿主細胞死亡之分子機制研究
The molecular mechanism of betanodavirus-regulated host cell death
指導教授： 洪健睿
Hong, Jiann-Ruey
學位類別： 博士
Doctor
系所名稱： 生物科學與科技學院 - 生物科技研究所
Institute of Biotechnology
論文出版年： 2010
畢業學年度： 98
語文別： 英文
論文頁數： 142
中文關鍵詞： 神經壞死病毒 、粒線體 、內質網壓力 、細胞死亡 、蛋白B2
外文關鍵詞： betanodavirus, mitochondria, ER stress, cell death, protein B2
相關次數： 點閱：97  下載：0 
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    • 石斑魚為台灣重要高經濟價值養殖魚種，在魚苗孵育過程易受神經壞死病毒感染造成高死亡率，使漁業經歷重大經濟損失。魚體受到神經壞死病毒感染後，會在腦及視網膜出現空泡化的壞死病變，同時魚體會出現體色變黑及不正常螺旋泳動等病徵。
    在本實驗室過去研究中證實，神經壞死病毒感染會造成宿主細胞經由破壞粒線體膜電位而釋放細胞色素c的方式使細胞走向先凋亡後壞死的死亡路徑。然而，病毒感染的致死機制尚未十分清楚，值得進行深入研究。
    本論文針對病毒致死機制及病毒非結構性蛋白功能提出下列四項問題，並嘗試回答。 1. 神經壞死病毒是否會造成宿主細胞內質網壓力。 2. 內質網壓力是否包含在病毒所引起的粒線體主導死亡路徑。 3. 神經壞死病毒非結構性蛋白B2之位置及其致死機制之研究。
    在研究中發現，神經壞死病毒造成宿主細胞死亡機制如下：第一，先引發宿主產生內質網壓力而大量表現GRP78，而後GRP78會和病毒的RdRp相互作用而促進病毒之複製及病毒致死蛋白之表現。第二，內質網壓力所造成的Bcl-2表現下降、caspase-12的活化及病毒致死蛋白的表現皆使細胞經由喪失粒線體膜電位而走向粒線體主導的細胞死亡路徑。最後，本論文證實B2為一個細胞壞死的誘導因子，可促使Bax表現而使細胞經由粒線體膜電位喪失之路徑走向死亡。同時，也證實B2可利用其粒線體訊號胜肽(41RTFVISAHAA50) 進入粒線體而誘使粒線體喪失其功能，如膜電位喪失及ATP缺乏，使細胞走向能量缺失主導的細胞壞死路徑。
    從本論文研究中，希望能在神經壞死病毒感染的治病機制上能提供新的見解，並在病毒的防治上有所貢獻。

    Betanodaviruses cause viral nervous necrosis (VNN), an infectious neuropathological condition in fish that is characterized by necrosis of the central nervous system, including the brain and retina. This disease causes mass mortality, resulting in rapid and complete loss of fish in the hatchery, leading to serious economic losses for the aquaculture industry.
    In previous study, betanodavirus infection induces mitochondria-mediated necrotic cell death via cytochorme c release and viral death proteins expressed may be involved in this necrotic process. However, the upstream of mitochondria-mediated necrotic cell death and the mechanism of betanodavirus non-structural protein (B1 and B2) function are still ill understood.
    In this thesis, we asked following question and examined the possibility that (1) whether and why RGNNV induces ER stress response in infected-cell, (2) if ER stress response is involving in upstream of mitochondria-mediated necrotic cell death in RGNNV infected cell, (3) characterize and identify protein B2 mitochondrial targeting and its function.
    We found that the death process of RGNNV infection is through ER-mitochondria-mediate necrotic cell death. As follows: First, RGNNV infection induces ER stress and upregulates the expression of GRP78 and which interacts with viral RdRp to enhance virus replication and viral death factors (protein α and B2) expression. Then, downregulation of Bcl-2 and expression of viral death factor causes mitochondria-mediated necrotic cell death via loss of MMP and cytochorme c released. Additionally, protein B2 is a necrotic death factor that triggers MMP loss via upregulation of pro-apoptotic protein Bax expression. Protein B2 locates to mitochondria via 41 RTFVISAHAA50 signal peptide and then causes mitochondria dysfunction (MMP loss and ATP depletion) and triggers cell undergoing bioenergetic crisis and necrotic cell death. Our studies may provide some insights into the pathogenesis of RGNNV infection.

    Contents English abstract I Chinese abstract III Acknowledgments V List of publish paper VI Contents VII Chapter 1. Introduction 1 1.1 Viral nervous necrosis (VNN) and nervous necrosis virus (NNV) 1 1.1.1 Viral nervous necrosis 1 1.1.2 Nervous necrosis virus 1 1.2 Cell death mechanism 2 1.2.1 Apoptosis 2 1.2.2 Autophagic cell death 3 1.2.3 Necrotic cell death or necrosis 3 1.3 The ER stress response 4 1.3.1 The mechanism of ER stress response 4 1.3.2 Virus induces host ER stress response 5 1.3.3 ER chaperon and virus replication 5 1.4 Viral proteins regulate host cell death 6 1.4.1 Viral pro-cell death proteins 6 1.4.2 Viral anti-cell death proteins 9 1.5 Betabodavirus induce host cell death 11 1.5.1 Protein α as a post-necrotic death factor 11 1.5.2 The nonstructural protein B2 as a host RNA interference (RNAi) suppressor 12 1.5.3 The nonstructural protein B1 as a anti-necrotic death factor 12 1.6 Object and specific aim 13 Chapter 2. Materials and methods 14 2.1 Cells and virus 14 2.2 Western blot analysis 14 2.3 In situ staining for caspase-12 activation 15 2.4 Annexin V-FLUOS staining 15 2.5 siRNA for knockdowndown of grouper GRP78 (gGRP78) protein expression 16 2.6 Cloning of zfGRP78 and construction of EGFP-zfGRP78 fused-genes 17 2.7 Tracing of mitochondria of zfGRP78 localization in fish cells 17 2.8 Tracing of protein A localization with immunofluorescence assay 18 2.9 Immunoprecipitation assay 18 2.10 Total mRNA preparation 19 2.11 Northern blot analysis 19 2.12 Preparation of mitochondria from RGNNV-infected cells 20 2.13 Evaluation of mitochondrial membrane potential with a lipophilic cationic dye 20 2.14 Cloning and sequence analysis of RGNNV B2 21 2.15 Expression of the B2 recombinant protein 22 2.16 Preparation of a polyclonal antibody against B2 23 2.17 TdT-dUTP labeling 24 2.18 Identification of functions of EYFP-B2 fused genes in cell death 25 2.19 Plasmids construction and cell transfection 25 2.20 Immunofluorescence assay 26 2.21 Immunoelectron microscopy 27 2.22 ATP assay 27 2.23 NAD+/NADH ratio assay (Complex I activity assay) 28 2.24 Succinate dehydrogenase (SDH) activity assay (Complex II activity assay) 28 2.25 Maintenance of fish embryos in culture 29 2.26 Microinjection of EYFP and EYFP-B2 29 2.27 Apoptotic cell staining 29 2.28 Cell counts and statistical analyses 30 2.29 Selection of RGNNV B2-specific siRNA-containing cell lines 30 Chapter 3. Results 32 3.1 The molecular death mechanism of RGNNV infected cells 32 3.1.1 Does RGNNV infection activate ER stress response? 32 3.1.2 What is GRP78 role in RGNNV infection? 34 3.1.3 Does ER stress response leading to mitochondrial-mediated cell death? 39 3.1.4 Summary 42 3.2 Indentify RGNNV nonstructural proteins B2 function 44 3.2.1 Cloning of RGNNV B2 44 3.2.2 Where is RGNNV B2 localization? 44 3.2.3 What is RGNNV B2 function? 46 3.2.4 What death mechanism is induced by RGNNV B2? 48 3.2.5 What necrosis mechanism is included? 52 3.2.6 Does knockdown of RGNNV B2 affect RGNNV-induced cell death? 54 3.2.7 Summary 56 Chapter 4. Conclusion, discussion and future direction 58 4.1 Conclusion 58 4.2 Discussion 60 4.2.1 The molecular death mechanism of RGNNV infected cells 60 a. The effect of ER chaperone protein GRP78 on viral replication 60 b. Why gGRP78 interacts with RdRp at early-middle replication stage? 61 c. RGNNV-triggered ER stress signal regulates mitochondria -mediated cell death at middle replication stage 62 d. Conclusion 63 4.2.2 Indentify RGNNV nonstructural proteins B2 function 64 a. A motif of the RGNNV B2 protein is required for mitochondrial targeting during the early replication stage of infection 65 b. Protein B2 induces MMP loss and produces a mitochondrial energy crisis 66 c. Viral proteins induce mitochondrial disruption and cellular death 67 4.3 Future direction 69 4.3.1 Regulation of host death by viral anti- and pro-cell death proteins 69 4.3.2 How ER chaperon GRP78 enhance RGNNV replication? 70 4.3.3 RNAi approach may be a potential agent to control VNN disease 71 Chapter 5. Reference 74 List of figures Fig. 1. Morphological ultrastructural features of cell death by transmission electron microscopy 89 Fig. 2. Identification of RGNNV infection induces ER stress responses in fish cells 90 Fig. 3. RGNNV induces caspase-12 activation 91 Fig. 4. The percentage of caspase-12 activated cells at each time point is shown in control and RGNNV-infected cells 92 Fig. 5. Caspase 12 activated stain of RGNNV-infected GF-1 cells treated or not treated with caspase 12 inhibitor 93 Fig. 6. The percentage of caspase 12 activated cell 94 Fig. 7. Phase-contrast and fluorescence images show annexin V-labeled death cells at 48h and 72h p.i. 95 Fig. 8. The percentage of annexin V positive cells for RGNNV-infected cells treated with caspase 12 inhibitor. 96 Fig. 9. Viral protein expression pattern in infected-cells treatment with caspase 12 inhibitor 97 Fig.10. Identification of knockdown of GRP78 by siRNA affect on viral replication 98 Fig. 11. Analysis of gGRP78 expression level by Western blot analysis 99 Fig. 12. The viability of GF-1 cells infected with RGNNV with siNegative and sigGRP78 transfection 100 Fig. 13. The virus titer of GF-1 cells infected with RGNNV with siNegative and sigGRP78 transfection 101 Fig. 14. Analysis of gGRP78 expression level by Western blot analysis 102 Fig. 15. Identification of overexpression of GRP78 affect on viral replication 103 Fig. 16. The viability of EGFP and EGFP-zfGRP78 transfected GF-1 cells infected with RGNNV 104 Fig. 17. Analysis of viral titer revealed overexpression of zfGRP78 can enhance viral replication with RGNNV infection 105 Fig. 18. Tracing of zfGRP78 mitochondrial localization with RGNNV infection 106 Fig. 19. Identification of gGRP78 was targeted to the mitochondrial membrane in RGNNV infected GF-1 cells at 48 h p.i. 107 Fig. 20. Identification of zfGRP78 interacted with RGNNV RNA dependent RNA polymerase at middle replication stage 108 Fig. 21. Identification of gGRP78 interacts with RdRp (protein A) from RGNNV-infected cells 109 Fig. 22. The doses dependent of GRP78 regulates viral protein expression 110 Fig. 23. GRP78 regulates viral protein expression 111 Fig. 24. Identification of the replication ratios of RGNNV genomic RNA1 and RNA3 in RGNNV-infected GF-1 cells untreated or treated with VT 112 Fig. 25. The virus titer of GF-1 cells infected with RGNNV with VT treatment 113 Fig. 26. sigGRP78 block GRP78 synthesis, reduce viral protein expression and reverses Bcl-2 down-regulation at a middle-late replication stage 114 Fig. 27. VT block GRP78 synthesis, reduce viral protein expression and reverses Bcl-2 down-regulation at a middle-late replication stage 115 Fig. 28. GRP78-mediated ER stress signal induces mitochondrial-mediated cell death 116 Fig. 29. The percentage of MMP loss cells for RGNNV-infected cells 117 Fig. 30. Blockage of GRP78-mediated ER stress can inhibit caspase-12 activation at middle replication stage 118 Fig. 31. Identification of VT (1μg/mL) treatment can block caspase-12 cleavage from pro-caspase-12 at 48 h pi. as determined by Western blot analysis 119 Fig. 32. Identification of VT treatment can block caspase-12 activity 120 Fig. 33. The viability of negative control, RGNNV-infected and VT-treated plus RGNNV-infected cells was determined at 48 h pi in triplicate 121 Fig. 34. RGNNV induces an ER stress-mediated cell death cascade 122 Fig. 35. Cloning and identification of RGNNV B2 as an early expression gene in fish liver cells 123 Fig. 36. Identification of RGNNV protein B2 as an early expression protein and its localization during infection in fish cells 124 Fig. 37. EYFG-B2 fused protein (traced directly, by immuno EM, and by MitoTracker dye) was identified as a hydrophobic mitochondrial targeting protein in GF-1 cells 125 Fig. 38. Identification of the different mutant forms of protein B2 and their localization in GF-1 cells 126 Fig. 39. The B2 protein induces the apoptotic cell death in fish cells 128 Fig. 40. Determination of whether B2 induces post-apoptotic necrotic cells in GL-av cells 129 Fig. 41. Protein B2 in mitochondria induces cell death 130 Fig. 42. B2 upregulates the pro-apoptotic gene Bax in fish cells 131 Fig. 43. B2 protein induces loss of MMP in GL-av cells independent of cytochrome c release 132 Fig. 44. Protein B2 in mitochondria induces MMP loss 133 Fig. 45. zfBcl-xL blocked B2-induced mitochondrial disruption in fish cells 134 Fig. 46. Protein B2 in mitochondria can cause ATP depletion through inhibiting complex II activity 135 Fig. 47. Protein B2 induces ATP-depletion and death of zebrafish embryos 136 Fig. 48. Effective B2 knockdown following RGNNV infection was correlated with down regulation of Bax and prevention of PS exposure in fish cells 138 Fig. 49. Effective knockdown of B2 with RGNNV infection is correlated with prevention of the loss of MMP in fish cells 140 Fig. 50. A schematic illustrating our hypothesis of protein B2-induced necrotic death in RGNNV-infected or B2-transfected cells 141 List of table Table. 1. The RGNNV B2 sequence primers used in this study 142

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