Cellular Activation and Apoptosis in Response to Foreign Cytoplasmic DNA

病毒是简单的有机体。它们在细胞内生长，需要宿主细胞蛋白进行复制。病毒只有自己的几种蛋白质，并迅速进化来改变这些蛋白质。因此，对免疫系统来说，识别病毒感染是具有挑战性的。最近，人们已经认识到，病毒的遗传物质(DNA或RNA)是由免疫系统检测的。一种识别病毒双链DNA的新途径正在出现。哺乳动物细胞的遗传物质(DNA)是在细胞膜结合的细胞核中发现的。细胞核外细胞质中DNA的存在是不正常的，被检测到是病毒感染的迹象。这要么会导致细胞死亡，要么会激活产生抗病毒分子。我们已经从细胞质中鉴定出一种能与DNA特异结合的蛋白质。这种名为X的蛋白质在被引入细胞后的5分钟内被发现与外源DNA有关。在这个项目中，我们建议确认X识别外源DNA，并启动细胞激活或死亡。在这个过程中X与之结合的其他分子将被识别出来。该项目涉及健康和疾病以及生物技术方面的一些问题。在基因治疗和生物技术中，DNA都被引入细胞中，以使这些细胞能够制造特定的蛋白质。细胞认为引入的DNA是一种潜在的病毒感染，它的反应方式限制了所需蛋白质的生产。狼疮是一种自身免疫性疾病，循环中的DNA水平很高。在小鼠模型中，X被认为是一种与狼疮相关的蛋白质。我们认为被细胞摄取的DNA是被X识别的，这导致了疾病。了解DNA在细胞质中的识别方式，可能会为生物技术中的基因治疗和蛋白质生产开发更有效的过程，以及更有效的狼疮和抗病毒治疗。

Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DNA) is found within the membrane-bound nucleus of the cell. The presence of DNA outside the nucleus in the cytoplasm is abnormal, and is detected as an indication of viral infection. This causes either death of the cell, or activation to produce anti-viral molecules. We have identified a protein from the cytoplasm of cells which binds specifically to DNA. This protein, X is found in association with foreign DNA within 5 minutes of it being introduced into the cell. In this project we propose to confirm that X recognises foreign DNA and initiates cellular activation or death. Other molecules to which X binds during this process will be identified. This project is relevant to a number of problems in health and disease as well as biotechnology. In both gene therapy and biotechnology, DNA is introduced into cells in order to allow those cells to make specific proteins. The cell sees the introduced DNA as a potential viral infection, and it responds in ways which limit the production of the desired proteins. Lupus is an autoimmune disease with high levels of DNA in circulation. X is proposed as a protein involved lupus in mouse models. We suggest that DNA taken up by cells is recognised by X and this contributes to the disease. Understanding the means by which DNA is recognised in the cytoplasm may allow the development of much more efficient processes for gene therapy and protein production in biotechnology, and more effective lupus and antiviral therapies.