Defining the roles and functional interdependencies of linear ubiquitin-related deubiquitinases and LUBAC in TNFR1 signalling

人体由数十亿个细胞组成，这些细胞相互交流。细胞交流的一种方式是通过一个细胞产生的信息因子，通过细胞之间的空间，最终结合到另一个细胞的表面。接收消息传递因子的单元将适当地响应该因子。这些因素在不同类型的免疫细胞之间的交流中尤其重要，而且在免疫细胞和其他细胞之间的交流方式中也尤为重要。通常这些因素会刺激接收细胞的反应，从而提醒免疫系统。在某些情况下，接收单元被通信因素杀死。然而，垂死细胞自身的反应是以特定因子的形式发出强大的信号，这些因子从垂死细胞中释放出来。这些高度有效的沟通因素被称为“损伤”或“危险”信号，代表了免疫系统可以参与的一些最强大的手段。细胞间通讯中最重要的因子之一是肿瘤坏死因子（TNF）。TNF对于对抗人类已知的最致命的感染之一至关重要，这种感染是由引起结核病的传染性病原体引起的。然而，考虑到肿瘤坏死因子的非凡力量，当它被解除管制时，它也会造成严重的损害，这也许并不奇怪。发现TNF可导致多种自身免疫性疾病，包括类风湿关节炎、克罗恩病和牛皮癣，就是例证。因此，患有这些疾病的患者通常受益于抑制TNF的药物治疗。这些药物非常昂贵，它们也完全阻断TNF的作用，而不仅仅是TNF的致病后果，而不干扰TNF的理想活性。我们的研究计划的目的是更好地了解肿瘤坏死因子的生物学特性，以及肿瘤坏死因子对接受细胞的刺激如何导致不同的结果，以便在未来，我们可以更精确地针对肿瘤坏死因子生物学的致病方面。根据接收细胞的组成，TNF可以触发一个警告其他细胞的信号，包括免疫细胞，但保持它们的完整，或者它可以触发细胞死亡，然后通过释放上述危险信号以不同的方式警告免疫系统。TNF与接收细胞结合的确切结果由接收细胞内的因素决定，我们最近确定了调节这一结果的三个因素。这些因子具有共同的功能，以前并不知道它们共同作用来确定TNF刺激细胞的结果。我们最近进行的实验使我们得出结论，这些因素中的每一个，除了在TNF刺激结果的调节中发挥共同功能外，还可能在所谓的“TNF信号传导”中具有“私人”功能。这里提出的研究目的是确定哪些功能是由这些因素共同发挥作用的，以及它们如何具体发挥其功能，以及哪些功能是由它们“私下”发挥作用的。我们还想揭示这些蛋白质的哪些部分分别负责“公共”和“私人”功能，以及破坏这些因素的特定部分如何影响细胞对TNF刺激的反应。我们想在分子和机械水平上理解这一点，也想在细胞系统上，最终在活的有机体上理解这一点。我们设想，更好地理解TNF刺激的功能结果，这是由我们在这里提出的研究的因素决定性地控制的，将有助于能够区分TNF的理想功能和不希望的功能，从而有助于开发治疗策略，使我们能够特异性地针对那些导致疾病的TNF功能。

The human body is made up of billions of cells which communicate with each other. One way for cells to communicate is via messaging factors that are produced by one cell, travel through the space between cells and finally bind to the surface of another cell. The cell that receives the messaging factor will respond to the factor as appropriate. Such factors are particularly important in the communication of different types of immune cells with each other but also in the way immune cells and other cells communicate with each other. Usually these factors stimulate a response from the receiving cell which alerts the immune system. In some cases the receiving cell is killed by the communication factor. However, the dying cell itself responds by sending out powerful signals in the form of specific factors that are released from the dying cell. These highly potent communication factors are known as "damage" or "danger" signals and represent some of the most powerful means by which the immune system can be engaged.One of the most important factors in cell-to-cell communication is the tumour necrosis factor (TNF). TNF is crucial for fighting off one of the deadliest infections known to humankind which is caused by infectious agent that causes tuberculosis. However, given the extraordinary power of TNF, it is perhaps not surprising that this factor can also cause severe damage when it is deregulated. This is exemplified by the discovery that TNF is causative for several autoimmune diseases including rheumatoid arthritis, Crohn's disease, and psoriasis. Consequently, patients suffering from these diseases often benefit from treatment with drugs that inhibit TNF. These drugs are very costly and they also block the effects of TNF completely rather than only the disease-causing consequences of TNF without interfering with the desirable activities of TNF. The aim of our research programme is to better understand the biology of TNF and how stimulation of a receiving cell by TNF leads to different outcomes so that, in the future, we can target the disease-causing aspects of the biology of TNF more precisely.Depending on the receiving cell's make-up, TNF can either trigger a signal that alerts other cells, including immune cells, but keeps them intact or it can trigger cell death which can then alert the immune system in a different way by the release of the afore-mentioned danger signals. The precise outcome of TNF binding to the receiving cell is determined by factors within the receiving cell and we recently identified three factors which regulate this outcome. These factors have a common function and were previously not known to act together to define the outcome of a cell's stimulation by TNF. Our recently performed experiments led us to conclude that each one of these factors, apart from serving a common function in the regulation of the outcome of TNF stimulation, may also have "private" functions in the so called "TNF signalling". The aim of the research proposed here is to identify which of these functions are served by these factors in common and how do they fulfil their function specifically but also which functions are served by them "privately". We also want to uncover which parts of these proteins are responsible for the "common" and "private" functions, respectively, and how disrupting defined parts of these factors affects the cell's response to stimulation by TNF. We want to understand this at the molecular and mechanistic level but also in cellular systems and, ultimately, in the living organism. We envisage that a better understanding of the functional outcomes of stimulation by TNF, which is decisively controlled by the factors we propose to study here, will contribute to being able to distinguish the desired from the undesired functions of TNF molecularly and, consequently, to the development of therapeutic strategies which allow us to specifically target those TNF functions which cause disease.