title: Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Huang
authors.forename: Junming
authors.initials: J
authors.lastname: Ren
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: He
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Li
authors.forename: Jianhui
authors.initials: J
authors.lastname: Ma
authors.forename: Wanze
authors.initials: W
authors.lastname: Chen
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhou
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Yang
authors.forename: Su-Qin
authors.initials: SQ
authors.lastname: Wu
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases