Journal article
MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, Rebecca Wilson, Tencho Tenev, Lucie Laurien, Chun Kim, Kunzah Jamal, Sidonie Wicky John, Gianmaria Liccardi, Diep Chau, James M Murphy, Gabriela Brumatti, Rebecca Feltham, Manolis Pasparakis, John Silke, Pascal Meier
MOLECULAR CELL | CELL PRESS | Published : 2017
Abstract
TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inh..
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Awarded by Breast Cancer Now
Awarded by World Wide Cancer Research grant
Awarded by MRC
Awarded by ERC
Awarded by NHMRC
Awarded by Australian Government NHMRC IRIISS
Awarded by Victoria Cancer Agency mid-career fellowship
Awarded by Biotechnology and Biological Sciences Research Council
Awarded by Medical Research Council
Awarded by Worldwide Cancer Research
Funding Acknowledgements
We would like to thank M. Gaestel for tissue from Mk2<SUP>-/-</SUP> mice. We thank members of the Meier, Silke, and Pasparakis laboratories for helpful discussions and the CECAD Transgenic Core Facility for CRISPR/Cas9 mutagenesis in mouse zygotes. R.W., G.L., and T.T. are supported by Breast Cancer Now CTR-QR14-007. I.J. is supported by a World Wide Cancer Research grant (14-1328) and Breast Cancer Now CTR-QR14-007. A. A. is supported by the MRC grant MR/M019217/7. P.M. acknowledges NHS funding to the NIHR Biomedical Research Centre. M.P. acknowledges funding from the ERC (grant agreement no. 323040). N.L is supported by World Wide Cancer Research grant 15-0042. This work was funded by NHMRC grants 1025594, 1046984, 1081221, and 1081376 and was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (9000220). J.S. is supported by fellowship 1107149 from the NHMRC. G.B. is supported by a Victoria Cancer Agency mid-career fellowship (VCA-MCRF15027). J.M.M. is supported by fellowship 1105754 from NHMRC. R.F. acknowledges funding from NHMRC 1081272.