臺灣博碩士論文加值系統

面對外來入侵病原的威脅，先天性免疫是宿主的第一道防線。為了即時做出反應，先天性免疫反應機制以模式識別受器 (pattern recognition receptors，PRRs) 辨認病原菌的病原相關分子模式 (pathogen-associated molecular patterns，PAMPs)。在所有模式識別受器中，RLRs (RIG-I like receptors) 在對抗病毒的功能上扮演舉足輕重的角色。先前我們實驗室發現 PIM1 這個絲胺酸/蘇胺酸激酶 (serine/threonine kinase) 可以透過其激酶活性抑制 RLRs 的訊息傳導，且推測其作用點可能在 RIG-I 或其上游。此外，先前的研究亦證明在體外 (in vitro) PIM1與 RIG-I 會有交互作用，且 PIM1 會將 RIG-I 進行磷酸化。本篇論文主要是以體內 (in vivo) 實驗為主，首先我利用外送表現的方式再度確認 RIG-I 與 PIM1 蛋白發生的交互作用，並且在仙台病毒 (SeV) 感染的情況下，此交互作用仍然存在；但觀察細胞內生性 PIM1 與 RIG-I 交互作用時，卻發現 PIM1 主要是與 RIG-I 一個經選擇性切割 (alternative splicing) 產生的異形體 (isoform) 有較強的交互作用，與全長 RIG-I 的交互作用反而較弱。磷酸化方面，同樣以外送表現證實 RIG-I 會受到 PIM1 的磷酸化；而在內生性 RIG-I 磷酸化的研究中，我們以慢病毒方式降低 (knock down) PIM1 表現，並在考量 RIG-I 相對表現量的情況下，發現在 PIM1 基因降低細胞內，其 RIG-I 磷酸化比例明顯低於控制組，故推測內生性 PIM1 可能也會對內生性 RIG-I 進行磷酸化作用。實驗結果更進一步顯示，外送表現之 PIM1 會對外送表現的 RIG-I 增加泛素化，並且使其降解；然而在相同情況下內生性 RIG-I 的總表現量卻未減少。由於我們目前尚未能成功偵測內生性 RIG-I 之泛素化現象，故內生性 RIG-I 是否不會受 PIM1 影響而改變泛素化及降解現象則尚待後續實驗加以證明。

Innate immunity is the first line of defenses to protect host from pathogen infection. In innate immunity, the “pattern recognition receptors (PRRs)” recognize pathogens by sensing their pathogen-associated molecular patterns (PAMPs). Among the PRRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) play significant roles in antiviral responses. Our lab has previously identified PIM1, a serine/threonine kinase and a proto oncogene, as a negative regulator of the RLRs signaling pathway. We have demonstrated in vitro that PIM1 may directly acts on RIG-I or on the molecules upstream of it, and that RIG-I interacts with PIM1 and is phosphorylated by PIM1. In this study, I examined the interaction between PIM1 and RIG-I, and the PIM1-mediated phosphorylation of RIG-I under in vivo condition. Ectopic expression results show that PIM1 and RIG-I interact with each other in the presence or absence of Sendai virus (SeV) infection. Interestingly, however, the endogenous PIM1 interacts more strongly with a RIG-I spliced variant, previously reported to be generated by alternative splicing of the RIG-I mRNA, than with the full-length RIG-I. The ectopic expression data also show that PIM1 can phosphorylate RIG-I by its kinase activity, whereas PIM1-knockdown decreases the relative phosphorylation level of endogenous RIG-I. Finally, our data show that PIM1 expression facilitates the ectopically expressed RIG-I undergoing ubiquitination and degradation, whereas the same condition does not affect the steady state levels of endogenous RIG-I. However, we have not been able to detect the ubiquitination pattern of endogenous RIG-I, so we cann’t conclude at this moment that PIM1 does not induce endogenous RIG-I undergoing ubiquitination and degradation.

致謝 i
中文摘要 iii
英文摘要 iv
目錄 v
圖表目錄 vii
英文縮寫對照表 viii
第一章 緒論 1
第一節 先天免疫系統 (innate immune system) 與第一型干擾素系統
(Type I interferon system) 1
第二節 RLR 訊息傳遞路徑與調控 13
第三節 原致癌基因 (proto-oncogene) PIM1 激酶 15
第四節 前人研究與實驗目的 22
第二章 實驗材料與方法 23
第一節 實驗材料 23
第二節 實驗方法 32
第三章 實驗結果 37
第一節 PIM1 蛋白與 RIG-I 蛋白在活體 (in vivo) 內的相互作用 (interaction) 37
第二節 在活體內 (in vivo) PIM1 蛋白對 RIG-I 蛋白之磷酸化
(phosphorylation) 39
第三節 在活體內 (in vivo) PIM1蛋白增加 RIG-I 蛋白之泛素化
(ubiguitination) 40
第四章 討論 44
圖表 51
附圖 59
參考文獻 65

圖一 在活體內 (in vivo) 外送表現 PIM1 與 RIG-I 之交互作用 51
圖二 Ｋ562 細胞以仙台病毒或 IFN-α 刺激後，內生性 PIM1 及 RIG-I 表
現量變化 52
圖三 在活體內 (in vivo) 細胞內生性 PIM1 與 RIG-I 之交互作用 53
圖四 在活體內 (in vivo) 外送表現PIM1 對外送 RIG-I 磷酸化之影響 54
圖五 在活體內 (in vivo) 基因敲落 PIM1 對 RIG-I 磷酸化之影響 55
圖六 在活體內 (in vivo) 外送表現 PIM1 對 RIG-I 泛素化之影響 56
圖七 在活體內 (in vivo) 外送表現 PIM1 增加 RIG-I 之 Lys48 泛素化 57
圖八 PIM1 並不會對細胞內生性 RIG-I 造成降解 58

附圖一 RIG-I 區域劃分及抑制狀態示意圖 59
附圖二 由 RIG-I 或 MDA5以及 RIG-I 與 MDA5 同時辨識之病毒 60
附圖三 RLR 訊息傳遞示意圖 61
附圖四 PIM1 藉由其激酶活性負向調控RLR活化之訊息路徑，且其作用點可
能在 RIG-I 或其上游 62

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