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. / Dondelinger, Yves; Delanghe, Tom; Priem, Dario; Wynosky-Dolfi, Meghan A; Sorobetea, Daniel; Rojas-Rivera, Diego; Giansanti, Piero; Roelandt, Ria; Gropengiesser, Julia; Ruckdeschel, Klaus; Savvides, Savvas N; Heck, Albert J R; Vandenabeele, Peter; Brodsky, Igor E; Bertrand, Mathieu J M.
In: NAT COMMUN, Vol. 10, No. 1, 15.04.2019, p. 1729.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
AU - Dondelinger, Yves
AU - Delanghe, Tom
AU - Priem, Dario
AU - Wynosky-Dolfi, Meghan A
AU - Sorobetea, Daniel
AU - Rojas-Rivera, Diego
AU - Giansanti, Piero
AU - Roelandt, Ria
AU - Gropengiesser, Julia
AU - Ruckdeschel, Klaus
AU - Savvides, Savvas N
AU - Heck, Albert J R
AU - Vandenabeele, Peter
AU - Brodsky, Igor E
AU - Bertrand, Mathieu J M
PY - 2019/4/15
Y1 - 2019/4/15
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Caspase 8/genetics
KW - Cell Line
KW - I-kappa B Kinase/metabolism
KW - Immunity/physiology
KW - Mice
KW - Models, Immunological
KW - Phosphorylation
KW - Receptor-Interacting Protein Serine-Threonine Kinases/chemistry
KW - Serine/chemistry
KW - Yersinia
KW - Yersinia Infections/immunology
U2 - 10.1038/s41467-019-09690-0
DO - 10.1038/s41467-019-09690-0
M3 - SCORING: Journal article
C2 - 30988283
VL - 10
SP - 1729
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -