臺灣博碩士論文加值系統

Orf virus (ORFV) OV20.0 is an antagonist of interferon (IFN). It inhibits activation of protein kinase (PKR), which suppresses viral protein synthesis during infection. OV20.0 and PKR harbor dsRNA binding domain (RBD) and are classified as dsRNA binding proteins (DRBP). It has been proposed that DRBPs regulate cell physiology by formation protein dimer. Adenosine deaminases acting on RNA 1 (ADAR1) catalyzes deamination of adenosine (A) to produce inosine (I) in dsRNA substrate. Due to its nature of dsRNA binding, we postulated that OV20.0 possibly interacts with ADAR1. In the present study, the association of OV20.0 with ADAR1 was evidenced for the first time. Interestingly, ADAR1 translocated and colocalized with N terminal truncated OV20.0 in cytoplasm. Among RBDs, several residues are highly conserved and that may directly contribute to dsRNA binding. We found the OV20.0 with lysine 160 residue replaced with alanine in its RBD has completely different features from wild type in many aspects of counteracting host innate immunity, including loss of binding ability with dsRNA and ADAR1. Subsequently, whether the OV20.0 interaction interferes with ADAR1’s A-to-I editing was accessed. It turned out that OV20.0 is a suppressor of deaminase activity of ADAR1. During virus infection, ADAR1 acts as an inhibitor of PKR. Increasing ADAR1 further enhanced inhibition of PKR activation mediated by OV20.0. Moreover, ADAR1 plays a proviral role in ORFV infection, possibly via inhibiting PKR activation. These observations indicate ADAR1 is a novel OV20.0 interacting partner, and shed light on the hierarchy of such multimolecular interaction and the potential effect on their mutual functions.

Contents
中文摘要 i
Abstract ii
Introduction 1
1. Orf virus 1
2. E3 proteins and Interferon (IFN) 2
3. The dsRNA dependent protein kinase (PKR) 3
4. OV20.0 and PKR 4
5. OV20.0 and other DRBP 6
6. ADAR1 7
7. NF90 8
8. Aims of the study 9
Material and method 11
1. Cloning procedure 11
1.1 General procedure 11
1.2 ADAR1 constructs 11
1.3 OV20.0 constructs 12
1.4 mCherry based gluR-B R/G reporter construct 14
2. Cell culture 14
3. Virus and infection 14
4. Transfection 15
5. FLAG-immunoprecipitation (IP) 15
6. dsRNA (polyI:C) pull down 16
7. Induction of PKR phosphorylation 16
8. Western blot analysis 16
9. Immunofluorescence assay (IFA) 17
Result 18
1. OV20.0 interacts with ADAR1, NF90, and NF45 via its RBD 18
2. ADAR1 interacts with OV20.0 via its RBDs 19
3. dsRNA is not necessary for the interaction of OV20.0 and ADAR1 20
4. OV20.0-GFP colocalizes with ADAR1 20
5. Key residues reserved on the RBD regions of OV20.0, PKR, PACT and ADAR1 21
6. K160A failed to interact with PKR and ADAR1, and suppress RNAi. 22
7. OV20.0 forms dimer via RBD and K160 is not the key residue for dimerization 23
8. OV20.0 disrupts ADAR1 A to I editing 24
9. ADAR1 plays a proviral role in ORFV infection 25
Discussion 27
1. OV20.0 interacts with ADAR1 27
2. Cellular distribution of OV20.0 and ADAR1 29
3. Highly conserved residues in RBDs 30
4. Functional assay of K160A mutant. 31
5. Modulation of RNAi by OV20.0 and ADAR1 32
6. OV20.0 disrupts A-to-I editing 33
7. ADAR1 and PKR and OV20.0 35
Reference 37
Figures 56
Appendix 72
Primer list 72
ADAR1 constructs 72
OV20.0 constructs 73
RNAi experiment 74
mCherry based R/G reporter 74
Antibodies used in this study 75

Figure Contents
Fig 1. Interaction of ORFV OV20.0 with cellular proteins. 57
Fig 2. Region of ADAR1 involved in OV20.0 interaction. 59
Fig 3. Cellular distribution of OV20.0 and ADAR1. 61
Fig 4. Key residues involved in dsRNA binding activity of OV20.0. 63
Fig 5. K160 is a key residue of OV20.0 for counteracting host defense system. 66
Fig 6. OV20.0 interferes with ADAR1’s A-to-I editing. 68
Fig 7. ADAR1 plays a proviral role upon ORFV infection. 71

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