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MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
- Source :
- Molecular Cell
- Publication Year :
- 2017
-
Abstract
- Summary 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.<br />Graphical Abstract<br />Highlights • Phosphorylation of RIPK1 by MK2 acts as survival checkpoint in TNF signaling • TNF-induced activation of MK2 results in global RIPK1 phosphorylation • MK2-mediated phosphorylation suppresses RIPK1 kinase activation and cell death • Complex-II originates from RIPK1 in complex-I as well as cytosolic RIPK1<br />Jaco et al. show that MK2 directly phosphorylates RIPK1 at residue S321, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway.
- Subjects :
- RIPK1
Fas-Associated Death Domain Protein
TNF
necroptosis
Apoptosis
p38
Protein Serine-Threonine Kinases
Transfection
Article
caspase-8
MK2
Mitogen-Activated Protein Kinase 14
Necrosis
cytokine
Animals
Humans
Phosphorylation
complex-II
Mice, Knockout
Caspase 8
Dose-Response Relationship, Drug
Tumor Necrosis Factor-alpha
Intracellular Signaling Peptides and Proteins
NF-kappa B
MAP Kinase Kinase Kinases
Mice, Inbred C57BL
IAPs
cell death
Multiprotein Complexes
Receptor-Interacting Protein Serine-Threonine Kinases
RNA Interference
HT29 Cells
Signal Transduction
Subjects
Details
- ISSN :
- 10974164
- Volume :
- 66
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular cell
- Accession number :
- edsair.pmid..........aa1a624843a81e6e067725049d8ebda7