TBK1 在 TLR3/4訊息傳遞中扮演之角色

Toll like receptors (TLRs) 訊息傳遞所產生的前發炎細胞激素(pro-inflammatory cytokines)以及第一型干擾素(type I interferon)對於宿主的先天性免疫(innate immunity)扮演非常重要的角色。而TLRs 受器主要是透過辨識一些病原菌相關的物質來啟動其訊息傳遞，而這些病原菌相關的物質又被稱為PAMPs (pathogen-associated molecular patterns)。TLRs的訊息主要是透過兩個含有 TIR domain的轉接蛋白傳遞，包括MyD88 及 TRIF。其中，MyD88 已經知道對於典型的NF-κB (canonical NF-κB)活化以及前發炎細胞激素的生成扮演關鍵性角色；而另一方面；在TRIF所引導的訊息傳遞當中，由過去的一些研究，已經了解TRIF可以徵招TBK1進而調控第一型干擾素的生成。此外，許多研究也指出，TRIF也參與在調控NF-κB 相關基因的表現，但是詳細的機制到目前為止並不明瞭。在TBK1的研究中，已經知道TBK1屬於IKK 激脢 (kinase) 家族的一員，長久以來， TBK1 被認為在調控第一型干擾素的生成以及先天性免疫的訊息傳遞中是必要的。但是，TBK1在先天性免疫訊息傳遞中的其他功能尚未明瞭。為了解TBK1在TLR 訊息傳遞中是否具有其他功能，我們使用LPS或是 poly I:C刺激巨噬細胞(Macrophages)並發現到TBK1會被進一步活化，同時我們也發現TBK1對於NF-κB活性是非常重要的。另一方面，我們也透過酵母雙雜交系統( yeast-two-hybrid screening)找到了新的TBK結合蛋白。而且在我們的實驗當中，我們證實，在LPS 刺激之後，TBK1會與與此蛋白質結合並可能進一步的調控TBK1的後轉譯修飾並進一步活化NF-κB活性。以上的實驗結果說明: 受LPS或poly I:C 活化後， TBK1對於調控巨噬細胞的NF-κB活化和部分NF-κB相關基因表現，扮演關鍵性的角色。這個研究也提供新的觀點讓我們能夠更深入去了解TLR的訊息傳遞以及其調控機制。

關鍵字

TLR訊息傳遞

並列摘要

Toll like receptors (TLRs) is of central importance for providing the first line of host defense, and controlling the initiation and determination of the adaptive immune response. TLRs initiate the signal transduction through sensing variety pathogen derived molecules terms PAMPs (pathogen-associated molecular patterns). The signals are transmitted by two major TIR containing adaptors, MyD88 and TRIF. It has been suggested that MyD88 is crucial for canonical NF-κB activation and pro-inflammatory cytokine induction, whereas TRIF is important for TBK1 activation and upregulation of type I interferon responsive genes. Recently, TRIF-signaling has been shown to be indispensable for expressions of NF-κB-mediated genes, but the molecular mechanism is still elusive. TBK1/NAK is a serine/threonine kinase that belongs to the IkB kinase (IKK) family. TBK1 has long been recognized as a key kinase required for production of type I interferon and interferone-responsive genes in many innate immune signaling, but not much is known about its other physiological functions. In this study, we uncovered a novel function of TBK1 in TLR3/4 signalings. Our data demonstrated that LPS or polyIC is able to induce TBK1 activation and then modulate NF-κB activity. In addition, we identified a new TBK1-interacting protein by using the yeast-two hybrid screening. The novel TBK1-interacting protein associates with TBK1 and processes post-translational modification after LPS stimulation. Taken together, our findings reveal that LPS- or polyIC- induce TBK1 activation which is required for NF-κB activity and production of some, if not all, NF-κB-mediated genes in macrophages. This study should provide new insights to the TLR signaling and its regulation.

並列關鍵字

TBK1, TLR3, TLR4

參考文獻

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TBK1 在 TLR3/4訊息傳遞中扮演之角色

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