Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis

• Published in: Cell research Vol. 23; no. 8; pp. 994 - 1006
• Main Authors: Wu, Jianfeng, Huang, Zhe, Ren, Junming, Zhang, Zhirong, He, Peng, Li, Yangxin, Ma, Jianhui, Chen, Wanze, Zhang, Yingying, Zhou, Xiaojuan, Yang, Zhentao, Wu, Su-Qin, Chen, Lanfen, Han, Jiahuai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2013; Nature Publishing Group
• Subjects: 631/45/127/1220; 631/80/82/2344; 631/80/86; Amino Acid Chloromethyl Ketones - pharmacology; Animals; Apoptosis; Base Sequence; Biomedical and Life Sciences; Cell Biology; Cell Line; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Life Sciences; Lipopolysaccharides - toxicity; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Mitogen-Activated Protein Kinase Kinases - metabolism; Necrosis; NF-kappa B - metabolism; NF-κB; Original; original-article; Protein Kinases - deficiency; Protein Kinases - genetics; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - deficiency; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factors - metabolism; 坏死性; 基因敲除; 小鼠; 巨噬细胞; 白细胞介素; 肿瘤坏死因子; 胚胎成纤维细胞; apoptosis; Mlkl; Rip3; TNF; mice; necroptosis
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2013.91

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 develop- ment. 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 abil- ity to activate NF-KB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides （LPS）, respectively. Consis- tently, Mlkl-deficient macrophages and mice exhibited normal interleukin-lp （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.