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Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

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Abstract
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.
Keywords
NF-KAPPA-B, OUTER PROTEIN-P, DOMAIN KINASE, APOPTOSIS, NECROPTOSIS, COMPLEX, ACTIVATION, NECROSIS, PATHWAY, BETA

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Chicago
Dondelinger, Yves, Tom Delanghe, Dario Priem, Meghan A Wynosky-Dolfi, Daniel Sorobetea, Diego Rojas Rivera, Piero Giansanti, et al. 2019. “Serine 25 Phosphorylation Inhibits RIPK1 Kinase-dependent Cell Death in Models of Infection and Inflammation.” Nature Communications 10.
APA
Dondelinger, Y., Delanghe, T., Priem, D., Wynosky-Dolfi, M. A., Sorobetea, D., Rojas Rivera, D., Giansanti, P., et al. (2019). Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. NATURE COMMUNICATIONS, 10.
Vancouver
1.
Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D, Rojas Rivera D, et al. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. NATURE COMMUNICATIONS. 2019;10.
MLA
Dondelinger, Yves et al. “Serine 25 Phosphorylation Inhibits RIPK1 Kinase-dependent Cell Death in Models of Infection and Inflammation.” NATURE COMMUNICATIONS 10 (2019): n. pag. Print.
@article{8613616,
  abstract     = {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.},
  articleno    = {1729},
  author       = {Dondelinger, Yves and Delanghe, Tom and Priem, Dario and Wynosky-Dolfi, Meghan A and Sorobetea, Daniel and Rojas Rivera, Diego and Giansanti, Piero and Roelandt, Ria and Gropengiesser, Julia and Ruckdeschel, Klaus and Savvides, Savvas and Heck, Albert JR and Vandenabeele, Peter and Brodsky, Igor E and Bertrand, Mathieu},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keywords     = {NF-KAPPA-B,OUTER PROTEIN-P,DOMAIN KINASE,APOPTOSIS,NECROPTOSIS,COMPLEX,ACTIVATION,NECROSIS,PATHWAY,BETA},
  language     = {eng},
  pages        = {16},
  title        = {Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation},
  url          = {http://dx.doi.org/10.1038/s41467-019-09690-0},
  volume       = {10},
  year         = {2019},
}

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