Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis
Open Access
- 9 July 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 23 (8), 994-1006
- https://doi.org/10.1038/cr.2013.91
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.This publication has 47 references indexed in Scilit:
- DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRACell Host & Microbe, 2012
- IAPs limit activation of RIP kinases by TNF receptor 1 during developmentThe EMBO Journal, 2012
- Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 KinaseCell, 2012
- The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death PathwaysCell, 2012
- Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012Cell Death & Differentiation, 2011
- Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington's diseaseCell Death & Disease, 2011
- Multiple death pathways in TNF-treated fibroblasts: RIP3- and RIP1-dependent and independent routesCell Research, 2011
- Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced InflammationCell, 2009
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death PathwayCell, 2008