Journal Article

MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death

Bertrand, Mathieu J. M., Delanghe, Tom, Dondelinger, Yves, Vandenabeele, Peter, Bruggeman, Inge, Priem, Dario, Rojas-Rivera, Diego, Delvaeye, Tinneke, Van Herreweghe, Franky

2017

Overview

TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF. Dondelinger et al. and Menon et al. show that MAPKAP kinase-2 (MK2) phosphorylates RIPK1 to regulate TNF-mediated cell death as well as RIPK1 signalling in inflammation and bacterial infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/95 / 38/44 / 38/70 / 38/77 / 631/250/256 / 631/80/458/1733 / 631/80/82/23 / 631/80/82/2344 / 64/60 / 82/29 / Animals / Apoptosis / Apoptosis - drug effects / Cancer Research / Cell Biology / Cell death / Cell Line / Cell survival / Cellular signal transduction / Cytological research / Cytosol - enzymology / Cytotoxicity / Deactivation / Developmental Biology / Disease Models, Animal / Enzyme Activation / Female / Fibroblasts - drug effects / Fibroblasts - enzymology / Fibroblasts - pathology / Genetic aspects / Inactivation / Inflammatory diseases / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Life Sciences / Mice / Mice, Inbred C57BL / Mortality / Necroptosis / Necrosis / Phosphorylation / Phosphotransferases / Properties / Protein Kinase Inhibitors - pharmacology / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Receptors, Tumor Necrosis Factor, Type I - agonists / Receptors, Tumor Necrosis Factor, Type I - metabolism / Serine / Shock - chemically induced / Shock - enzymology / Shock - pathology / Shock - prevention & control / Signal transduction / Signal Transduction - drug effects / Signaling / Stem Cells / Time Factors / Tumor necrosis factor / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha - toxicity