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

定义线性泛素相关去泛素酶和 LUBAC 在 TNFR1 信号传导中的作用和功能相互依赖性

• 批准号: MR/S00811X/1
• 负责人: Henning Walczak
• 金额: $ 325.49万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS00811X%2F1
• 关键词: Defining; roles; functional; interdependencies; linear

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.

人体由数十亿个细胞组成，这些细胞相互交流。细胞进行通信的一种方式是通过一个细胞产生的信息传递因子，通过细胞之间的空间旅行，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相互交流中特别重要，而且在免疫细胞和其他细胞之间的交流方式中也很重要。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，接收小区被通信因素杀死。然而，垂死的细胞本身通过以从垂死细胞释放的特定因子的形式发出强大的信号来做出反应。肿瘤坏死因子（tumor necrosis factor，TNF）是细胞间相互作用的重要因子之一，也是免疫系统中最重要的信号之一。肿瘤坏死因子（tumor necrosis factor，TNF）是细胞间相互作用的重要因子。肿瘤坏死因子是至关重要的战斗之一，人类已知的最致命的感染，这是由传染性病原体引起的结核病。然而，考虑到TNF的非凡力量，当它被解除管制时，这种因素也会导致严重的损害，这也许并不奇怪。这通过TNF是几种自身免疫性疾病（包括类风湿性关节炎、克罗恩病和牛皮癣）的病因的发现来例证。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，并且它们还完全阻断TNF的作用，而不仅仅是TNF的致病后果，而不干扰TNF的期望活性。我们的研究项目的目的是更好地了解TNF的生物学以及TNF对接收细胞的刺激如何导致不同的结果，以便将来我们可以更精确地针对TNF生物学的致病方面。根据接收细胞的组成，TNF可以触发警告其他细胞的信号，包括免疫细胞，但保持它们完整，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与受体细胞结合的确切结果是由受体细胞内的因素决定的，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，并且以前不知道它们一起作用以定义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，除了在调节TNF刺激的结果中起共同作用外，还可能在所谓的“TNF信号传导”中具有“私人”功能。这里提出的研究的目的是确定这些功能是由这些因素共同服务的，以及它们如何具体地履行其功能，但也有哪些功能是由它们“私下”服务的。我们还希望揭示这些蛋白质的哪些部分分别负责“共同”和“私人”功能，以及破坏这些因子的定义部分如何影响细胞对TNF刺激的反应。我们希望在分子和机械水平上理解这一点，但也希望在细胞系统中理解这一点，并最终在生物体中理解这一点。我们设想，更好地了解TNF刺激的功能结果，这是决定性的控制因素，我们建议在这里研究，将有助于能够区分所需的TNF分子的不需要的功能，因此，治疗策略的发展，使我们能够专门针对这些TNF功能，导致疾病。

项目成果

A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.

• DOI: 10.1073/pnas.2110557119
• 发表时间: 2022-04-26
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers.

在广泛的癌症中，有效的促凋亡组合疗法非常有效。

• DOI: 10.1038/s41418-021-00869-x
• 发表时间: 2022-03
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Montinaro A;Areso Zubiaur I;Saggau J;Kretz AL;Ferreira RMM;Hassan O;Kitzig E;Müller I;El-Bahrawy MA;von Karstedt S;Kulms D;Liccardi G;Lemke J;Walczak H
• 通讯作者: Walczak H

Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries.

• DOI: 10.1038/s41418-022-01059-z
• 发表时间: 2023-02
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Montinaro, Antonella;Walczak, Henning
• 通讯作者: Walczak, Henning

Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.

• DOI: 10.1172/jci170217
• 发表时间: 2023-11-01
• 期刊: The Journal of clinical investigation

Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis.

• DOI: 10.3390/cancers15030967
• 发表时间: 2023-02-03
• 期刊: Cancers
• 影响因子: 5.2