Bcl-2 regulates pyroptosis and necroptosis by targeting BH3-like domains in GSDMD and MLKL.,Cell Death Discovery

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Bcl-2 regulates pyroptosis and necroptosis by targeting BH3-like domains in GSDMD and MLKL.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41420-019-0230-2
Chong-Shan Shi ₁ , John H Kehrl ₁

Affiliation

Apoptosis is a form of programmed cell death in multicellular organisms. Bcl-2 prevents apoptosis and promotes cellular survival by neutralizing BH3 domain-containing proteins, which directly activate the pore-forming proteins BAX and BAK. However, Bcl-2 is not known to regulate other cell death effectors such as gasdermin D (GSDMD) or mixed lineage kinase domain-like (MLKL), whose activation causes pyroptosis and necroptosis, respectively. Here, we identify a BH3-like domain in both GSDMD and MLKL that mediates an interaction with B-cell lymphoma 2 (Bcl-2). The presence of Bcl-2 reduced GSDMD cleavage at D275 by caspase-1, 4 or 5, and enhanced the GSDMD cleavage at D87. The GSDMD D87 cleavage inactivates the pyroptotic execution program. The presence of Bcl-2 also limited RIP3 mediated phosphorylation of MLKL, which reduced MLKL oligomerization and tempered the induction of necroptosis. Our observations suggest that the presence of Bcl-2 limits the induction of three forms of cell death apoptosis, pyroptosis, and necroptosis.

中文翻译：

Bcl-2通过靶向GSDMD和MLKL中的BH3样结构域来调节细胞凋亡和坏死性坏死。

凋亡是多细胞生物中程序性细胞死亡的一种形式。Bcl-2通过中和含BH3结构域的蛋白质来防止细胞凋亡并促进细胞存活，该蛋白质直接激活成孔蛋白BAX和BAK。但是，尚不知道Bcl-2会调控其他细胞死亡效应因子，如加德敏D（GSDMD）或混合谱系激酶结构域样（MLKL），它们的激活分别引起发烧和坏死。在这里，我们在GSDMD和MLKL中都鉴定出一个BH3样结构域，该结构介导与B细胞淋巴瘤2（Bcl-2）的相互作用。Bcl-2的存在减少了caspase-1、4或5在D275处的GSDMD裂解，并增强了D87处的GSDMD裂解。GSDMD D87切割使焦磷酸执行程序失活。Bcl-2的存在也限制了RIP3介导的MLKL磷酸化，减少了MLKL的低聚反应并减轻了坏死病的诱导。我们的观察结果表明，Bcl-2的存在限制了三种形式的细胞死亡，凋亡，凋亡和坏死性细胞死亡的诱导。

更新日期：2019-12-09

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