登革病毒的感染會造成登革熱、登革休克症候群和登革出血熱等臨床疾病。目前還沒有有效的治療藥物或疫苗。因此，了解登革病毒的致病機制和宿主病毒間的相互作用，對於登革病毒所誘導的疾病之治療是至關重要的。第一型干擾素和數百種干擾素刺激基因可以對抗病毒感染。不幸地，已知登革病毒發展出能夠與宿主相互作用，並擺脫干擾素所介導的抗病毒反應的策略。而我們先前發現，整合素連接激酶 (Integrin-linked kinase, ILK)，一種絲氨酸/蘇氨酸蛋白激酶，是促進登革病毒複製的關鍵宿主因子。我們的證據顯示，登革病毒能夠透過ILK/Akt/NF-κB所誘發之細胞因子信號3 (SOCS3)，來負向調控第一型干擾素的信息傳遞訊號。然而，尚未清楚登革病毒是如何激活該整合素連接激酶所介導之機制。為了解決這個難題，我們將帶有個別登革病毒蛋白的質體轉染到人類肺癌細胞中，以研究它們在整合素連接激酶所調控路徑中的角色。實驗結果指出，當細胞大量表達登革病毒非結構蛋白1，2A，3和4A時，它們會誘發細胞因子信號3的表現量；而這樣的表現能夠被整合素連接激酶抑制劑所減緩。此外，由這些病毒非結構蛋白所上調的細胞因子信號3，能夠趨緩第一型干擾素所誘發的信號傳導及轉錄激活蛋白1 (STAT1)的活化，以及下游干擾素刺激基因的產生。儘管免疫共沈澱和共聚焦顯微成像試驗顯示，在細胞大量表達登革病毒非結構蛋白1，2A，3和4A時和干擾素連接激酶之間的相關性，但更顯著的在登革病毒感染的細胞中觀察到，登革非結構蛋白1和3與整合素連接激酶之間的相互作用。此外，我們還發現在登革病毒感染時，整合素連接激酶的末端錨蛋白重複序列對於誘發細胞因子信號3是很重要的。這指出登革病毒非結構蛋白可能可以結合到整合素連接激酶的末端錨蛋白重複序列上。綜合以上實驗結果，我們發現這些登革非結構蛋白，在調控整合素連接激酶所依賴的細胞因子信號3之誘發的潛在角色，並提供了能夠作為未來抗病毒藥物研發的策略。

Dengue virus (DENV) infection is responsible for causing clinical diseases as dengue fever, dengue shock syndrome, and dengue hemorrhagic fever. There are no effective treatments or vaccines currently. Therefore, understanding the dengue pathogenesis and host-virus interaction is crucial for developing treatments against DENV-induced diseases. Type-1 interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs) provide a defense against virus infection. Unfortunately, DENV was found to evolve strategies to interact with host factors and escape from IFN-mediated antiviral responses. We have previous found that integrin-linked kinase (ILK), a serine/ threonine protein kinase, is a crucial host factor for facilitating DENV replication. Our evidence revealed that DENV is able to regulate the negative feedback of IFN signaling via ILK/Akt/ERK/NF-κB-induced suppressor of cytokine signaling 3 (SOCS3) expression. However, it is unclear how DENV activates this ILK-mediated pathway. To solve this puzzle, we transfected individual plasmid cloned with each DENV protein into A549 cells to investigate their roles on ILK-induced SOCS3 expression. The results showed that ectopic expression of DENV NS1, NS2A, NS3, and NS4A induces increased expression of SOCS3, which is abolished by ILK inhibitor. The up-regulated SOCS3 by these DENV nonstructural proteins is able to attenuate IFN-induced STAT1 activation and downstream ISG production. Although the co-immunoprecipitation and the confocal assays demonstrated that ILK is associated with ectopic expressed DENV NS1, NS2A, NS3 and NS4A, significant interaction of ILK with DENV NS1 and NS3 was observed in DENV-infected cells. Furthermore, we also identified the N-terminal ankyrin (ANK) repeats of ILK is critical to induce SOCS3 during DENV infection. This suggests that DENV NS proteins may bind to ANK repeats of ILK. In conclusion, these results reveal the potential role of these DENV nonstructural proteins to regulate ILK-dependent-SOCS3 induction and provide the strategy for the future antiviral therapeutic drug development.

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