Ubiquitin networks in cell death regulation and non-apoptotic signalling

细胞死亡调节和非凋亡信号传导中的泛素网络

• 批准号: BB/L021684/1
• 负责人: Pascal Meier
• 金额: $ 44.3万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL021684%2F1
• 关键词: Ubiquitin; networks; cell; death; regulation

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.

泛素(Ub)的翻译后修饰是一种称为泛素化的过程，控制着细胞死亡和生存的重要方面。UB可以作为一个单一的部分或以聚合链的形式连接到促凋亡和抗凋亡的蛋白质上，在这些聚合链中，连续的泛素分子通过特定的异肽键相连。让人联想到密码，各种泛素修饰采用不同的构象，并导致不同的结果在细胞中。为了防止泛素化被结构性地开启，修饰被去除Ub加合物的去泛素化酶(DUB)逆转。虽然人们对Ub-附着的后果进行了深入的研究，但关于去除Ub-加合物的去结合酶的作用却知之甚少。拟议方案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动态平衡所需的细胞过程。我们将使用一系列连锁的遗传和生化方法来识别和表征调控caspase介导的细胞死亡和非凋亡信号的DUB。在一项初步研究中，我们确定了几个Dub，当移除时，可以抑制体内的细胞死亡。在这里，我们打算研究其中五个DUB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组成部分发挥作用。重要的是，越来越多的证据表明，caspase介导的信号传递产生与细胞环境沟通的信号，以协调补偿性增殖、组织再生和伤口愈合。因此，我们还将评估已识别的DUBS的丢失是否也会影响适应组织应激所需的caspase激活。综上所述，我们建议研究Ub网络的动力学和特异性，并研究Ub结合和去结合如何影响信号结果。解开DUBS如何调控细胞死亡和非凋亡信号是至关重要的，因为这些过程在动物发育和组织动态平衡中发挥着基本的生理作用。

项目成果

Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.

• DOI: 10.1038/s41467-021-23474-5
• 发表时间: 2021-06-07
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Garcia LR;Tenev T;Newman R;Haich RO;Liccardi G;John SW;Annibaldi A;Yu L;Pardo M;Young SN;Fitzgibbon C;Fernando W;Guppy N;Kim H;Liang LY;Lucet IS;Kueh A;Roxanis I;Gazinska P;Sims M;Smyth T;Ward G;Bertin J;Beal AM;Geddes B;Choudhary JS;Murphy JM;Aurelia Ball K;Upton JW;Meier P
• 通讯作者: Meier P

Novel biochemical, structural, and systems insights into inflammatory signaling revealed by contextual interaction proteomics.

• DOI: 10.1073/pnas.2117175119
• 发表时间: 2022-10-04
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

SUMO-mediated regulation of NLRP3 modulates inflammasome activity.

SUMO介导的NLRP3调节调节炎症体活性。

• DOI: 10.1038/s41467-018-05321-2
• 发表时间: 2018-08-01
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Barry R;John SW;Liccardi G;Tenev T;Jaco I;Chen CH;Choi J;Kasperkiewicz P;Fernandes-Alnemri T;Alnemri E;Drag M;Chen Y;Meier P
• 通讯作者: Meier P

PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.

• DOI: 10.1038/nm.4198
• 发表时间: 2016-11
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Brasó-Maristany F;Filosto S;Catchpole S;Marlow R;Quist J;Francesch-Domenech E;Plumb DA;Zakka L;Gazinska P;Liccardi G;Meier P;Gris-Oliver A;Cheang MC;Perdrix-Rosell A;Shafat M;Noël E;Patel N;McEachern K;Scaltriti M;Castel P;Noor F;Buus R;Mathew S;Watkins J;Serra V;Marra P;Grigoriadis A;Tutt AN
• 通讯作者: Tutt AN

Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation.

Drice限制了DIAP2介导的炎症信号传导和肠炎。

• DOI: 10.1038/s41418-021-00832-w
• 发表时间: 2022-01
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Kietz C;Mohan AK;Pollari V;Tuominen IE;Ribeiro PS;Meier P;Meinander A
• 通讯作者: Meinander A