Replication-dependent histone pre-mRNA misprocessing and innate immune sensing

点击翻译按钮获取中文摘要

Viruses are tiny organisms that are everywhere. In order to make more copies of themselves viruses infect the cells of other organisms, including humans. Being able to fight off viruses is absolutely necessary for our survival; simply put, if a person cannot do so, they will die. How do our cells realise that they are being infected by a virus? It turns out that the way we do this is by sensing the presence of viral genetic material (referred to as DNA and RNA) as the virus enters the cell. Much as a dog might bark to wake up the owner when a burglar breaks into a house, our cells 'raise the alarm' when they sense viral DNA and RNA by producing a very powerful chemical called interferon. Interferon acts as a kind of cellular disinfectant and is very good at killing virus. However, like a disinfectant, too much interferon can be dangerous, so that it is important that interferon is used carefully, and only when needed. Aicardi-Goutières syndrome (AGS) is the name of a severe disease that can affect children. Over the last 30 years, we have learned that AGS is associated with very high levels of interferon. As explained above, we know that interferon is normally only produced when we are infected with a virus. However, in AGS, there is no viral infection. The question arises then, why are levels of interferon so high in AGS? The answer to this question is explained in general terms by the fact that our own cells are full of our own DNA and RNA, which also has the potential to trigger the production of interferon. Because of this, safety mechanisms exist to minimise the risk that we might misinterpret our own DNA and RNA as virus. These mechanisms include dedicated 'waste-disposal' systems for getting rid of (old) self DNA and RNA, keeping self DNA and RNA separate from the alarm systems that sense viruses, and the marking of self DNA and RNA with a stamp saying 'self'. In brief, a person with AGS has an inherited problem with one of these mechanisms, so that the cells in a person with AGS confuse their own DNA or RNA with that coming from a virus. Very recently, we have identified a new cause of AGS, which is the subject of this grant application. Almost all cells in our body have a special compartment called the nucleus, the place in the cell where our genetic material (composed of DNA) is stored. This DNA is arranged in tiny thread-like structures called chromosomes. Chromosomes are coated by other chemicals, in particular a material called histone. We have discovered that some people with AGS are not able to make the correct amount of histone, and that this triggers the production of interferon. This is very interesting, because how the cell ensures that the genetic material in the nucleus does not trigger an interferon response is not properly understood. We intend to study the detailed mechanism of the disease in this new type of AGS. In doing so, our work should not only be of potential benefit to people with the devastating disease AGS, it will also shed light on a fundamental aspect of how human cells stay healthy.