Ubiquitin networks in cell death regulation and non-apoptotic signalling

泛素（Ub）的翻译后修饰，一个被称为泛素化的过程，控制着细胞死亡和存活的重要方面。Ub可以作为单个部分或以聚合物链的形式连接到促凋亡蛋白和抗凋亡蛋白，其中连续的泛素分子通过特异性异肽键连接。让人想起密码，各种泛素修饰采用不同的构象，并导致细胞中的不同结果。为了防止泛素化被组成型开启，修饰被去泛素化酶（DUB）逆转，去泛素化酶（DUB）切割掉Ub加合物。虽然深入研究了UB-附着的后果，但关于去除UB-加合物的解缀合酶的作用知之甚少。该计划的目的是揭示泛素信号是如何结合和编辑的，以调节正常发育和组织稳态过程中所需的细胞过程。我们将使用一系列连锁遗传和生物化学方法来识别和识别调控半胱天冬酶介导的细胞死亡和非凋亡信号的DUBs。在一项初步研究中，我们确定了几种DUB，当去除时，抑制体内细胞死亡。在这里，我们建议调查这些DUBs的生理作用和分子机制。特别是，我们将评估它们是否作为组织修复过程中不可或缺的和进化上保守的成分发挥作用。重要的是，越来越多的证据表明，半胱天冬酶介导的信号传导产生与细胞环境通信的信号的释放，以协调补偿性增殖、组织再生和伤口愈合。因此，我们还将评估鉴定的DUB的丢失是否也影响适应组织应激所需的半胱天冬酶活化。总之，我们建议调查的动力学和特异性的UB网络和研究如何UB共轭和去共轭信号的结果的影响。揭示DUBs如何调节细胞死亡和非凋亡信号传导是至关重要的，因为这些过程在动物发育和组织稳态中起着基本的生理作用。

The posttranslational modification with ubiquitin (Ub), a process referred to as ubiquitylation, controls important aspects of cell death and survival. Ub can be attached to pro- and anti-apoptotic proteins as a single moiety or in the form of polymeric chains in which successive ubiquitin molecules are connected through specific isopeptide bonds. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and lead to different outcomes in cells. To prevent ubiquitylation from being constitutively on, modifications are reversed by de-ubiquitylating enzymes (DUB) that cleave off the Ub adduct. While the consequence of Ub-attachment is intensely studied, little is known with regards to the effects of deconjugating enzymes that remove the Ub-adduct. The aim of the proposed programme is to unravel how the ubiquitin-signal is conjugated and edited to modulate cellular processes that are required during normal development and tissue homeostasis. We will use a series of interlocking genetic and biochemical approaches to identify and characterise DUBs that regulate caspase-mediated cell death and non-apoptotic signalling. In a pilot study we identified several DUBs that, when removed, suppress cell death in vivo. Here we propose to investigate the physiological role and molecular mechanism of five of these DUBs. Particularly, we will assess whether they function as integral and evolutionarily conserved components of the tissue repair process. Importantly, a growing body of evidence indicate that caspase-mediated signalling generates the release of signals that communicate with the cellular environment to coordinate compensatory proliferation, tissue regeneration and wound healing. Hence, we will also assess whether loss of the identified DUBs also affects caspase activation required for adaptation to tissue stress. Taken together, we propose to investigate the dynamics and specificity of Ub networks and study how Ub conjugation and deconjugation impact on signaling outcomes. Unravelling how DUBs regulate cell death and non-apoptotic signalling is critically important as these processes play fundamental physiological roles in animal development and tissue homeostasis.