Monocyte chemotactic protein-1-induced protein 1 (MCPIP1)，也被稱為Zc3h12a，在負向調控發炎反應上扮演一個重要的角色。MCPIP1 蛋白質包含著高度保存性的CCCH-type zinc finger domain 與Nedd4-BP1, YacP Nuclease(NYN) domain，分別具有RNA binding、ribonuclease (RNase) activity 及deubiquitinase (DUB) function 的特性。過去文獻指出，人類MCPIP1 蛋白質展現廣泛抑制多種RNA及DNA病毒感染的能力，包括Japanese encephalitis virus(JEV)、Dengue fever virus 2 (DEN-2)、sindbis virus、encephalomyocarditis virus及adenovirus。在本篇研究中，人類MCPIP1 蛋白質可以抑制A 型流感病毒(influenza virus; IAV)的感染。進一步利用不同MCPIP1 蛋白質突變型探討MCPIP1 各功能性domain 是否參與對抗IAV 感染的機制，不具RNase 及DUB功能的突變型MCPIP1 (D141N)、RNase (+)/DUB (-)的MCPIP1 (C157A)及RNase (-)/DUB (+)的MCPIP1 (D225/226A)皆失去抑制A 型流感病毒感染的能力。在CCCH type Zinc finger domain 發生突變的五種突變型中，西方墨點法顯示MCPIP1 (C306R)、(C312R)、(C318R)、(H322R)及(Δ305-325)皆無法抑制
A 型流感病毒的感染，但在病毒效價測定的結果中，MCPIP1 (C306R)、(C318R)及(H322R)仍保有抑制病毒複製的能力。proline-rich domain 缺失的突變型MCPIP1 (Δ458-536)不具有抑制A 型流感病毒感染的能力。而in vitro cleavage assay 的結果顯示，MCPIP1 蛋白質的RNase 活性無法降解IAV 的八段cRNA。A 型流感病毒感染A549 細胞會引誘proinflammatory molecules 的產生，但不會大量引發內生性MCPIP1 表現。綜合我們的實驗結果，在MCPIP1 蛋白質抑制A 型流感病毒感染過程中，需要RNase activity 及DUB function 同時存在，而RNA binding 及oligomerization 能力也參與其中。

摘要 V
Abstract VI
第一章 緒論 (Introduciton) 1
壹、流行性感冒病毒 (Influenza virus) 1
一、流行性感冒病毒之流行病學 1
二、流行性感冒病毒之分類 1
三、 A 型流行性感冒病毒構造及基因簡介 1
四、 A 型流行性感冒蛋白質功能簡介 3
五、流行性感冒病毒生活史 5
貳、 Monocyte chemotactic protein-induced protein 1 (MCPIP1) 6
一、 MCPIP1 簡介 6
二、 MCPIP1 分子結構 6
三、 MCPIP1 功能 7
參、研究動機 7
第二章 材料與方法 (Materials and methods) 9
壹、材料 9
一、病毒株 9
二、細胞株 9
三、抗體 9
貳、實驗方法 10
一、流感病毒的效價(titer)測定 10
二、質體構築 10
三、西方墨點法 (Western blot) 11
四、免疫螢光染色法 (Immunofluorescence assay) 12
五、即時定量反轉錄聚合酵素連結反應 (Real-time RT-Polymerase Chain
Reaction) 13
六、蛋白質萃取與純化 (protein extraction and purification) 13
七、 In vitro transcription 14
八、 In vitro RNA cleavage assay 14
第三章 實驗結果 15
一、 MCPIP1 蛋白質抑制A 型流感病毒之感染 15
二、突變型MCPIP1 (D141N)蛋白質無法抑制A 型流感病毒之感染 15
三、突變型MCPIP1 (C157A)及 MCPIP1 (D225/226A)無法抑制IAV 的感染16
四、 MCPIP1 蛋白質無法降解IAV 的complementary RNA (cRNA) 17
五、 MCPIP1 抑制IAV 的感染可能需要RNA 結合能力的參與 18
六、 MCPIP1 抑制IAV 的感染需要oligomerization 功能的參與 19
七、 IAV 感染引發細胞內TNF-a、MCP-1、IL-6 表，但卻無法有效誘導MCPIP1 的表現 19
第四章 討論 21
第五章 參考文獻(References) 25
第六章 目次圖表 (Figures list) 34
Figure 1. The construct of human monocyte chemotectic protein 1-induced protein
1 (MCPIP1) 34
Figure 2. The construct of human MCPIP1 mutant (Δ458-536) 35
Figure 3. The construction of human MCPIP1 CCCH-type Zinc finger domain mutant (C312R) 36
Figure 4. The construct of human MCPIP1 CCCH-type Zinc finger domain mutant
(C318R) 37
Figure 5. The construct of human MCPIP1 CCCH-type Zinc finger domain mutant
(H322R) 38
Figure 6. The construct of Flu-PB2-BamHI 39
Figure 7. The construct of Flu-PB1-HindIII 40
Figure 8. The construct of Flu-PA-AgeI 41
Figure 9. The construct of Flu-HA-AgeI 42
Figure 10.The construct of Flu-NP-AgeI 43
Figure 11.The construct of Flu-NA-HpaI 44
Figure 12.The construct of Flu-M-AgeI 45
Figure 13.The construct of Flu-NS-AgeI 46
Figure 14.The human monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) exhibits potent antiviral activity against IAV and human MCPIP1 (D141N)
mutant lost its antiviral effect against IAV. 47
Figure 15.Human MCPIP1 (D141N) mutant lost its antiviral effect against IAV. 48
Figure 16.Human MCPIP1 (C157A) and MCPIP1 (D225/226) mutants lost their antiviral effect against IAV. 49
Figure 17.Human MCPIP1 did not degrade IAV complementary RNA. 50
Figure 18.CCCH-type Zinc finger domain mutant MCPIP1 proteins have different
effect on IAV infection. 51
Figure 19.The proline-rich domain of human MCPIP1 is essential for its anti-IAV
activity. 52
Figure 20.Expression of human MCP-1, IL-6 and TNF-α are induced by IAV infection in A549 cells, but not MCPIP1. 53
TABLE 1. Summary of the function and anti-IAV activity of MCPIP1 mutants 54

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