Cellular Activation and Apoptosis in Response to Foreign Cytoplasmic DNA

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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.