The deubiquitinating enzymes CYLD and A20 as gate keepers of central nervous system homeostasis

去泛素化酶 CYLD 和 A20 作为中枢神经系统稳态的看门人

• 批准号: 500247271
• 负责人: Professor Dr. Ari Waisman
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/500247271?language=en
• 关键词: deubiquitinating; enzymes; CYLD; A20; gate

Lysine-63 ubiquitination is a post-translational modification that leads to the activation of the NFkB signaling pathway. Removal of these ubiquitin chains is performed by a class of proteases termed deubiquitinating (DUB) enzymes, representing an important mechanism to control NFkB activity. We and others have shown that the DUB enzymes A20 and CYLD regulate the NFkB pathway in a variety of immune cells, including T cells, B cells, dendritic cells as well as in different macrophage subsets, including particularly microglia cells. We recently reported that A20 plays a critical role in the function of microglia during steady state, where in the absence of A20, the microglia started to express genes associated with viral infection, which ultimately led to the invasion of the CNS by CD8+ T cells. Furthermore, mice lacking A20 in microglia presented with dysfunctional neuronal networks, which could be corrected by the elimination of the invading T cells. We have recently also generated mice that allow for the tissue-specific deletion or overexpression of CYLD. Preliminary data obtained with these mice shows that CYLD overexpression results in reduced entry of lymphocytes to the CNS during steady state. Furthermore, deletion of CYLD in microglia leads to increased invasion of the CNS by T cells, thus suggesting that CYLD and A20 may play a similar role for microglia function. In the frame of this grant proposal, we plan to further investigate the precise role of CYLD during microglia homeostasis. In addition, we want to test the different mice with microglial DUB mutations in a model of CNS autoimmunity in order to decipher the role of microglia in promoting pathogenic T cell responses and the possible contribution of dysregulated NFkB signaling in these processes. Finally, we aim to analyze the possible role for the investigated DUB enzymes in the process of ageing, using both mouse models and human post mortem material from healthy (aged) as well as Alzheimer’s Disease patients. Together, our proposed experiments aim to evaluate A20 and CYLD as potential regulators of microglia activity and function at steady state as well as during CNS inflammation associated with autoimmunity or ageing.

赖氨酸-63泛素化是一种翻译后修饰，导致NF κ B信号通路的激活。这些泛素链的去除由一类称为去泛素化（DUB）酶的蛋白酶进行，代表控制NF κ B活性的重要机制。我们和其他人已经表明，DU B酶A20和CYLD调节多种免疫细胞中的NF κ B途径，所述免疫细胞包括T细胞、B细胞、树突细胞以及不同的巨噬细胞亚群，特别包括小胶质细胞。我们最近报道，A20在稳态期间小胶质细胞的功能中起着关键作用，在没有A20的情况下，小胶质细胞开始表达与病毒感染相关的基因，最终导致CD 8 + T细胞侵入CNS。此外，在小胶质细胞中缺乏A20的小鼠表现出功能失调的神经元网络，这可以通过消除入侵的T细胞来纠正。我们最近还产生了允许组织特异性缺失或过表达CYLD的小鼠。用这些小鼠获得的初步数据显示，CYLD过表达导致稳态期间淋巴细胞进入CNS的减少。此外，小胶质细胞中CYLD的缺失导致T细胞对CNS的侵袭增加，从而表明CYLD和A20可能对小胶质细胞功能起类似的作用。在这个资助计划的框架内，我们计划进一步研究CYLD在小胶质细胞稳态中的确切作用。此外，我们希望在CNS自身免疫模型中测试具有小胶质细胞DUB突变的不同小鼠，以破译小胶质细胞在促进致病性T细胞应答中的作用以及这些过程中失调的NF κ B信号传导的可能贡献。最后，我们的目的是分析可能的作用，为调查DUB酶在衰老过程中，使用小鼠模型和人类尸检材料从健康（老年）以及阿尔茨海默病患者。总之，我们提出的实验旨在评估A20和CYLD作为稳态下以及与自身免疫或衰老相关的CNS炎症期间小胶质细胞活性和功能的潜在调节剂。