MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.
Wicky John, S
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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.
Version of record
Dose-Response Relationship, Drug
Fas-Associated Death Domain Protein
Intracellular Signaling Peptides and Proteins
MAP Kinase Kinase Kinases
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 14
Receptor-Interacting Protein Serine-Threonine Kinases
Tumor Necrosis Factor-alpha
Cell Death and Inflammation
License start date
Mol Cell, 2017, 66 (5), pp. 698 - 710.e5
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