Volume 23, No 8, Aug 2013
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 23 Issue 8, August 2013: 994-1006
ORIGINAL ARTICLES
Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis
Jianfeng Wu1,*, Zhe Huang1,*, Junming Ren1,*, Zhirong Zhang1, Peng He1, Yangxin Li1, Jianhui Ma1, Wanze Chen1, Yingying Zhang1, Xiaojuan Zhou1, Zhentao Yang1, Su-Qin Wu1, Lanfen Chen1 and Jiahuai Han1
1State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
Correspondence: Correspondence: Jiahuai Han, E-mail: jhan@xmu.edu.cn; jhan@scripps.edu*These three authors contributed equally to this work.
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-κB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides (LPS), respectively. Consistently, Mlkl-deficient macrophages and mice exhibited normal interleukin-1β (IL-1β), 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.
10.1038/cr.2013.91
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