Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis

被引：373

作者：

Wu, Jianfeng ^{[1
,2
]}

Huang, Zhe ^{[1
,2
]}

Ren, Junming ^{[1
,2
]}

Zhang, Zhirong ^{[1
,2
]}

He, Peng ^{[1
,2
]}

Li, Yangxin ^{[1
,2
]}

Ma, Jianhui ^{[1
,2
]}

Chen, Wanze ^{[1
,2
]}

Zhang, Yingying ^{[1
,2
]}

Zhou, Xiaojuan ^{[1
,2
]}

Yang, Zhentao ^{[1
,2
]}

Wu, Su-Qin ^{[1
,2
]}

Chen, Lanfen ^{[1
,2
]}

Han, Jiahuai ^{[1
,2
]}

机构：

[1] Xiamen Univ, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China

[2] Xiamen Univ, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China

来源：

CELL RESEARCH | 2013年 / 23卷 / 08期

基金：

中国国家自然科学基金;

关键词：

Mlkl; necroptosis; apoptosis; TNF; Rip3; mice; TUMOR-NECROSIS-FACTOR; MIXED-LINEAGE KINASE; MITOCHONDRIAL PERMEABILITY TRANSITION; CELL-DEATH; PROGRAMMED NECROSIS; INFLAMMATORY RESPONSE; DOMAIN-LIKE; RIP3; APOPTOSIS; DOWNSTREAM;

D O I：

10.1038/cr.2013.91

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development. Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their ability to activate NF-kappa B, ERK, JNK, and p38 in response to TNF and lipopolysaccharides (LPS), respectively. Consistently, Mlkl-deficient macrophages and mice exhibited normal interleukin-1 beta (IL-1 beta), IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis.

引用

页码：994 / 1006

页数：13

共 47 条

[1] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death [J].