2015-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647480摘要：蛋白質可逆的lysine 乙醯化（lysine acetylation）功能在調節基因表現扮演關鍵的角色。Histone deacetylases (HDACs) 除了有對於調節基因表現及histone 修飾等重要功能外，近期研究指出它對於發炎(inflammation) 與先天性免疫反應(innate immune response) 調控至關重要。已知HDAC1、HDAC2 及HDAC3 等則為正向調控STASs 下游之IFNAR 訊息傳遞路徑。最新的研究指出，HDAC6 主要表現在細胞質中，透過對於IRF-3 依賴與否兩種方式促進干擾素的生成。 在RNA 病毒感染過程中，藉由RIG-I like Receptor (RLR) family 偵測細胞質中PAMP RNA 對於干擾素生成甚為關鍵。除此之外，RLR 的抗病毒訊息傳遞具有清除對於Rhabdovirus, Paramyxovirus,Orthomyxovirus, Flavivirus 及Reovirus 等病毒感染的重要功能。先前，RLR 訊息傳遞路徑中重要的組成分子如RIG-I, 14-3-3ε及TRIM25 在未感染細胞的細胞質中被發現是乙醯化蛋白質。所以，我們欲研究在RNA 病毒感染時細胞質中去乙醯化的現象以及此現象對於先天性免疫反應抗病毒的貢獻，尤其對於RLR 抗病毒訊息傳遞的影響。此研究可以釐清細胞質中HDACs 的角色並了解在RNA 病毒感染時，HDAC 如何調控宿主細胞先天性抗病毒之免疫反應。<br> Abstract: Reversible lysine acetylation of nuclear proteins has been shown to play a key role in regulation gene expression. Besides the central functions in histone modifications and gene expression regulations, emerging roles of histone deacetylases (HDACs) in regulating inflammation and innate immune response have been revealed. HDAC1, HDAC2 and HDAC3 positively regulate STATs downstream of IFNAR signaling. In recent reports, HDAC6, which is predominantly in the cytoplasm, was reported to promote interferon productions in both IRF-3 dependent and -independent manners. During RNA virus infections, cytosolic PAMP RNA detections by the RIG-I-like Receptor (RLR) family are crucial in interferon production. Moreover, RLR anti-viral signaling has been shown to be important in the clearance of Rhabdovirus, Paramyxovirus, Orthomyxylvirus, Flavivirus and Reovirus infections. Previously, essential components of the RLR signaling pathway, such as RIG-I, 14-3-3ε and TRIM25, were reported as acetyl-proteins in the cytoplasm in the uninfected cells. Our preliminary data suggested that cytoplasmic HDACs play critical roles in IFN-β promoter activation. In addition, HDAC3 and HDAC6 could interact with RIG-I, and the deacetylation of RIG-I was essential for its activation. Based on these results, we hypothesize that cytoplasmic HDACs are essential for the activation of antiviral innate immunity. Therefore, we propose to investigate cytoplasmic deacetylation events during RNA virus infections, and how these events can contribute to anti-viral innate immunity, especially in the RLR anti viral signaling pathways. We will first investigate which HDACs are necessary for RIG-I activation and what is the determinate factor for RIG-I/HDAC complex formation during RNA virus infections. We will also investigate if 14-3-3ε and TRIM25 acetylation is controlling their activities. We will further study the molecular mechanisms of HDAC-dependent IFN-β promoter activation, and what the accessory proteins involved in these regulatory events are. Lastly, we would like to extend the study to assess if HDAC dependent IFN-β promoter activation is RLR pathway specific, and whether certain viruses may have developed strategies to antagonize cytoplasmic HDACs to avoid anti-viral innate immunity activation. We expect to elucidate the role for cytoplasmic HDACs. The virus and host processes that impact HDAC functions are likely to control anti-viral signaling pathway during RNA virus infections, and thus these studies may provide insightful strategies to current anti-viral and anti-inflammation therapies.抗病毒干擾素去乙醯化乙醯化