MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
AuthorJaco, I; Annibaldi, A; Lalaoui, N; Wilson, R; Tenev, T; Laurien, L; Kim, C; Jamal, K; John, SW; Liccardi, G; ...
Source TitleMolecular Cell
University of Melbourne Author/sLalaoui, Najoua; Murphy, James; Brumatti, Gabriela; Feltham, Rebecca; Silke, John
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsJaco, I., Annibaldi, A., Lalaoui, N., Wilson, R., Tenev, T., Laurien, L., Kim, C., Jamal, K., John, S. W., Liccardi, G., Chau, D., Murphy, J. M., Brumatti, G., Feltham, R., Pasparakis, M., Silke, J. & Meier, P. (2017). MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. MOLECULAR CELL, 66 (5), pp.698-+. https://doi.org/10.1016/j.molcel.2017.05.003.
Access StatusOpen Access
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 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.
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