人體中屬於先天性免疫系統的Pattern recognition receptors (PRRs)，如Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs)，可以辨識病原體具高保留性的產物Pathogen-associated molecular patterns (PAMPs)而引起免疫反應。病毒感染時，細胞質的RLRs，包含RIG-I及 MDA5，負責偵測病毒核醣核酸物質並引起抗病毒免疫反應。然而目前對於RLRs與其他分子的交互作用來調控抗病毒的機制仍有尚不清楚的地方需要進一步研究。我們實驗室先前的研究發現了一個新的調控先天性免疫反應的分子TAPE (TBK1-Associated Protein in Endolysosomes)，匯集Toll-like receptor 3 (TLR3), Toll-like receptor 4 (TLR4),及 RLRs的訊息傳遞而影響第一型干擾素的生成及抗病毒反應。透過搜尋人類基因體的資料庫，我們發現了一個具有與TAPE分子達54.2%蛋白質序列相似度的分子，我們稱之TAPE-L (TAPE-like protein)。在此篇研究中，我主要探討TAPE-L在RLR所調控的訊息傳遞路徑中所扮演的角色。我的實驗結果顯示，TAPE-L參與在NF-kB、IFN-b及Erk路徑中。默化(knockdown)細胞內TAPE-L表現會阻礙transfected polyI:C 活化RIG-I和表達MDA5所調控的IFN-b及NF-kB報導基因的活化。在transfected polyI:C 刺激時，RIG-I所調控的細胞激素IFN-b、RNATES及IL-8的生成也受到TAPE-L蛋白表現減少而下降。實驗同時比較TAPE-L和TAPE兩者關係得到一有趣的發現，即當細胞受到transfected polyI:C 刺激時，TAPE-L會參與在RIG-I及MDA5調控的IFN-b及NF-kB兩者活化路徑，而TAPE卻只會影響IFN-b路徑。我進一步發現TAPE-L會和 IPS-1、RIG-I或MDA5在細胞內形成分子團並且加成和RIG-I、MDA5及IPS-1所活化的IFN-b反應。總結以上實驗結果，我發現TAPE-L會參與RIG-I、MDA5調控的訊息路徑。在未來的研究，我們可以利用細胞及動物實驗探討TAPE-L 在對抗病毒感染的各種角色。

The innate immune system senses pathogen invasion by multiple pattern recognition receptors (PRRs), like Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), to recognize highly conserved pathogen-associated molecular patterns (PAMPs). Cytosolic RLRs, including RIG-I and MDA5, are responsible for detecting viral RNA (vRNA) species to trigger antiviral immune responses during viral infection. The mechanisms of how RLRs cooperate with other molecules in regulating antiviral immunity remain to be further investigated. Previous work from our lab revealed a novel innate immune regulator called TAPE (TBK1-Associated Protein in Endolysosomes), which links the TLR3, TLR4, RIG-I and MDA5 pathways to IFN-b induction. A TAPE-like protein termed TAPE-L with 54.2% similarity to TAPE was found in the human genome. Here I report that TAPE-L plays a key role in the RLR pathways. TAPE-L was shown to involve in the NF-kB, IFN-b and ERK pathways. Knockdown of TAPE-L impaired RIG-I-mediated IFN-b and NF-kB promoter activation by transfected polyI:C stimulation. TAPE-L knockdown also impaired MDA5-mediated IFN-b and NF-kB by overexpression of MDA5. TAPE-L knockdown inhibited RIG-I-mediated IFN-b, RANTES and IL-8 cytokine production by transfected polyI:C stimulation and the antiviral response against vesicular stomatitis virus. Interestingly, TAPE-L was involved in regulating both the IFN- and NF-kB pathways during RIG-I and MDA5 signaling while TAPE was only required for IFN-b activation. Furthermore, TAPE-L interacted and synergized with IPS-1, RIG-I or MDA5 to activate IFN-b. Collectively, my work demonstrates that TAPE-L acts as an innate immune regulator in the RIG-I and MDA5 pathways. In the future, we can determine the implication of TAPE-L during virus infection in vitro and in vivo.

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