当前位置: X-MOL 学术EMBO J. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis
The EMBO Journal ( IF 11.4 ) Pub Date : 2021-10-26 , DOI: 10.15252/embj.2019103718
Zikou Liu 1, 2 , Laura F Dagley 1, 2 , Kristy Shield-Artin 1, 2 , Samuel N Young 1 , Aleksandra Bankovacki 1, 3 , Xiangyi Wang 1, 2 , Michelle Tang 4, 5 , Jason Howitt 4, 5 , Che A Stafford 6 , Ueli Nachbur 1, 2 , Cheree Fitzgibbon 1 , Sarah E Garnish 1, 2 , Andrew I Webb 1, 2 , David Komander 1, 2 , James M Murphy 1, 2 , Joanne M Hildebrand 1, 2 , John Silke 1, 2
Affiliation  

Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor-interacting serine/threonine protein kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here, we show that necroptosis-specific multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin-insoluble cell fraction comprising organellar and plasma membranes and protein aggregates. Appearance of this ubiquitylated MLKL form can be reduced by expression of a plasma membrane-located deubiquitylating enzyme. Oligomerization-induced MLKL ubiquitylation occurs on at least four separate lysine residues and correlates with its proteasome- and lysosome-dependent turnover. Using a MLKL-DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licences MLKL auto-activation independent of necroptosis signalling in mouse and human cells. Therefore, in addition to the role of ubiquitylation in the kinetic regulation of MLKL-induced death following an exogenous necroptotic stimulus, it also contributes to restraining basal levels of activated MLKL to avoid unwanted cell death.

中文翻译:

寡聚化驱动的 MLKL 泛素化拮抗坏死性凋亡

混合谱系激酶结构域样 (MLK​​L) 是不依赖半胱天冬酶的程序性细胞死亡形式(称为坏死性凋亡)的执行者。受体相互作用的丝氨酸/苏氨酸蛋白激酶 3 (RIPK3) 磷酸化 MLKL,触发 MLKL 寡聚化、膜易位和膜破裂。MLKL 在坏死性凋亡过程中也经历了泛素化,但这一事件的机制和意义均未得到证实。在这里,我们表明 MLKL 的坏死性凋亡特异性多单泛素化发生在其激活和寡聚化之后。泛素化 MLKL 在包含细胞器和质膜以及蛋白质聚集体的洋地黄皂苷不溶性细胞部分中积累。这种泛素化 MLKL 形式的出现可以通过质膜定位的去泛素化酶的表达来减少。寡聚化诱导的 MLKL 泛素化发生在至少四个独立的赖氨酸残基上,并与其蛋白酶体和溶酶体依赖性转换相关。使用 MLKL-DUB 融合策略,我们表明从 MLKL 中组成性去除遍在蛋白允许 MLKL 自动激活,而不受小鼠和人类细胞中坏死性凋亡信号的影响。因此,除了泛素化在外源性坏死刺激后 MLKL 诱导死亡的动力学调节中的作用外,它还有助于抑制活化 MLKL 的基础水平以避免不必要的细胞死亡。我们表明,从 MLKL 中组成性去除遍在蛋白允许 MLKL 自动激活,而与小鼠和人类细胞中的坏死性凋亡信号无关。因此,除了泛素化在外源性坏死刺激后 MLKL 诱导死亡的动力学调节中的作用外,它还有助于抑制活化 MLKL 的基础水平以避免不必要的细胞死亡。我们表明,从 MLKL 中组成性去除遍在蛋白允许 MLKL 自动激活,而与小鼠和人类细胞中的坏死性凋亡信号无关。因此,除了泛素化在外源性坏死刺激后 MLKL 诱导死亡的动力学调节中的作用外,它还有助于抑制活化 MLKL 的基础水平以避免不必要的细胞死亡。
更新日期:2021-12-01
down
wechat
bug