MiR-302c调节抗流感病毒天然免疫通路的研究

发布时间：2018-03-27 10:38

本文选题：甲型流感病毒　切入点：miR-302c　出处：《武汉大学》2016年博士论文

【摘要】：MicroRNAs (miRNAs)是存在于真核细胞内的18-24个核苷酸长度的RNA分子。在动物中,单链miRNA结合到靶基因]mRNA的3’非翻译区抑制mRNA的翻译或导致mRNA的降解。近年来各种研究表明,miRNA在流感病毒的复制和机体抗病毒免疫中起作用。尽管有microRNA在流感病毒感染和免疫过程中起作用,关于miR-302c和病毒以及先天免疫系统之间的关系尚未被阐明。在我们的研究中,我们探索了miR-302家族在病毒的复制中的功能,发现miR-302家族中的miR-302c在病毒的复制中起关键作用。我们还进一步研究了miR-302c与miR-520e的关系,尽管有研究指出miR-520e在肝癌细胞中通过靶向NIK发挥其功能,但在我们的研究中发现,在A549细胞中]miR-520e并不能通过靶向NIK 3'UTR序列来增强病毒的复制。因此我们推测,在病毒感染过程中,不同的病毒调节不同miRNA的表达来调控NIK的表达与干扰素的诱导。NF-κB诱导激酶(NIK)也被称为MP3K14,是p100加工生成p52所必需的蛋白激酶,也是NF-κB非经典通路的重要组成部分。最近的一些研究证实了NIK在先天免疫和炎症反应中的作用。在我们的研究中发现,miR-302c影响了p65和p50的入核,而对ReIB和p52的入核没有影响。我们的研究结果与先前的报道一致,即NIK能参与调控经典NF-κB通路,虽然其确切的调控机制仍有待继续研究。近年来,大量的研究已经揭示了病毒诱发Ⅰ型干扰素信号通路的机制。尽管我们对流感病毒激活天然免疫反应的机制已经有很多了解,但是对于microRNA和流感病毒诱导的天然免疫之间的关系仍然不甚清楚。在我们的研究中,我们观察到流感病毒通过抑制miR-302c诱导了IFN-β的表达。我们的数据提供了流感病毒激活Ⅰ型干扰素的一种新的机制。总之,在本论文的研究中,我们证明了之前未被人所知的流感病毒调节干扰素β表达的机制。我们发现流感病毒能够抑制miR-302c表达,从而诱导干扰素β信号通路。我们的研究还证明miR-30302c可以抑制NIK的表达,并通过靶向NIK阻止NF-κB的入核,从而导致对IFN-β及下游信号通路的抑制。我们的结果揭示了在流感病毒感染中miR-302c扮演的新角色,也为流感病毒的感染提供了一个潜在的治疗策略。
[Abstract]:MicroRNAs is an 18-24 nucleotide length RNA molecule found in eukaryotic cells. Single strand miRNA binds to target gene] the 3'untranslated region of mRNA inhibits the translation of mRNA or leads to the degradation of mRNA. Recent studies have shown that miRNAs play a role in influenza virus replication and body antiviral immunity, despite the presence of microRNA in influenza viruses. Infection and immune processes play a role, The relationship between miR-302c and viruses and innate immune systems has not been clarified. In our study, we explored the role of the miR-302 family in viral replication. We also further studied the relationship between miR-302c and miR-520e. Although some studies have shown that miR-520e can function through targeted NIK in hepatoma cells, we have found that. In A549 cells, miR-520e does not enhance the replication of the virus by targeting the NIK 3'UTR sequence. Different viruses regulate the expression of different miRNA to regulate the expression of NIK and interferon induced. NF- 魏 B induced kinase NIKK, also known as MP3K14, is the protein kinase necessary for p100 to produce p52. It is also an important part of the NF- 魏 B nonclassical pathway. Some recent studies have confirmed the role of NIK in innate immune and inflammatory response. In our study, we found that miR-302c affected the entry of p65 and p50. Our results are consistent with previous reports that NIK is involved in regulating the classical NF- 魏 B pathway, although its exact regulatory mechanism remains to be further studied in recent years. A great deal of research has revealed the mechanism of interferon type I signaling pathway induced by viruses, although we already know a lot about the mechanism of influenza virus activating innate immune response. But the relationship between microRNA and influenza virus-induced innate immunity remains unclear. We have observed that influenza virus induces IFN- 尾 expression by inhibiting miR-302c. Our data provide a new mechanism for influenza virus to activate interferon type 1. We have demonstrated the previously unknown mechanism by which influenza viruses regulate the expression of interferon beta. We have found that influenza viruses can inhibit the expression of miR-302c and thus induce the signaling pathway of interferon beta. Our study also shows that miR-30302c can inhibit the expression of NIK. The inhibition of IFN- 尾 and its downstream signaling pathway by targeting NIK may lead to the inhibition of NF- 魏 B. our results reveal that miR-302c plays a new role in influenza virus infection and provides a potential therapeutic strategy for influenza virus infection.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R392

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