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

病毒是无处不在的微小有机体。为了复制更多的自身，病毒感染包括人类在内的其他有机体的细胞。能够击退病毒对我们的生存是绝对必要的；简单地说，如果一个人做不到这一点，他们就会死亡。我们的细胞是如何意识到自己正被病毒感染的？事实证明，我们做到这一点的方法是在病毒进入细胞时感知病毒遗传物质(称为DNA和RNA)的存在。就像窃贼闯入房子时，狗可能会叫来叫醒主人一样，当我们的细胞通过产生一种名为干扰素的非常强大的化学物质来感知病毒DNA和RNA时，它们就会发出警报。干扰素作为一种细胞消毒剂，非常擅长杀灭病毒。然而，就像消毒剂一样，太多的干扰素可能是危险的，所以谨慎使用干扰素是很重要的，而且只有在需要的时候才使用。艾卡迪-古蒂埃综合征(AGS)是一种可影响儿童的严重疾病的名称。在过去的30年里，我们了解到AGS与非常高水平的干扰素有关。如上所述，我们知道干扰素通常只有在感染病毒时才会产生。然而，在AGS中，没有病毒感染。那么问题就来了，为什么AGS中的干扰素水平如此之高？这个问题的答案大体上可以用这样一个事实来解释：我们自己的细胞中充满了我们自己的DNA和RNA，这也有可能触发干扰素的产生。正因为如此，安全机制的存在可以最大限度地减少我们可能将自己的DNA和RNA误解为病毒的风险。这些机制包括专用的“废物处理”系统，用于清除(旧的)自己的DNA和RNA，使自己的DNA和RNA与感知病毒的警报系统分开，以及用印有“自我”的邮票标记自己的DNA和RNA。简而言之，AGS患者的其中一种机制存在遗传问题，因此AGS患者体内的细胞会将自己的DNA或RNA与来自病毒的DNA或RNA混淆。最近，我们发现了AGS的一个新原因，这是这次赠款申请的主题。我们体内的几乎所有细胞都有一个特殊的隔间，称为细胞核，细胞中的遗传物质(由DNA组成)就是在这里储存的。这种DNA排列在称为染色体的微小线状结构中。染色体被其他化学物质包裹，特别是一种称为组蛋白的物质。我们发现，一些AGS患者不能制造正确数量的组蛋白，这会触发干扰素的产生。这是非常有趣的，因为细胞如何确保细胞核中的遗传物质不会引发干扰素反应并没有得到正确的理解。我们打算研究这种新型AGS的详细发病机制。通过这样做，我们的工作不仅应该对患有毁灭性疾病AGS的人有潜在的好处，它还将揭示人类细胞如何保持健康的一个基本方面。

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.