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Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
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Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
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Journal Article
Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
2019
Overview
RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of
Yersinia
infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.
RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/1
/ 82/51
/ 82/58
/ 82/80
/ 82/83
/ 96/109
/ 96/2
/ 96/21
/ 96/95
/ Animals
/ Caspase
/ Humanities and Social Sciences
/ I-kappa B Kinase - metabolism
/ I-kappa B Kinase - physiology
/ Kinases
/ Mice
/ Mimicry
/ Mutation
/ Receptor-Interacting Protein Serine-Threonine Kinases - chemistry
/ Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
/ Receptor-Interacting Protein Serine-Threonine Kinases - physiology
/ Science
/ Serine
/ Yersinia
