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

Yves Dondelinger, Tom Delanghe, Dario Priem, Meghan A. Wynosky-Dolfi, Daniel Sorobetea, Diego Rojas-Rivera, Piero Giansanti, Ria Roelandt, Julia Gropengiesser, Klaus Ruckdeschel, Savvas N. Savvides, Albert J. R. Heck, Peter Vandenabeele, Igor E. Brodsky and Mathieu J. M. Bertrand ()
Additional contact information
Yves Dondelinger: VIB Center for Inflammation Research
Tom Delanghe: VIB Center for Inflammation Research
Dario Priem: VIB Center for Inflammation Research
Meghan A. Wynosky-Dolfi: University of Pennsylvania
Daniel Sorobetea: University of Pennsylvania
Diego Rojas-Rivera: VIB Center for Inflammation Research
Piero Giansanti: University of Utrecht
Ria Roelandt: VIB Center for Inflammation Research
Julia Gropengiesser: University Medical Center Eppendorf
Klaus Ruckdeschel: University Medical Center Eppendorf
Savvas N. Savvides: VIB Center for Inflammation Research
Albert J. R. Heck: University of Utrecht
Peter Vandenabeele: VIB Center for Inflammation Research
Igor E. Brodsky: University of Pennsylvania
Mathieu J. M. Bertrand: VIB Center for Inflammation Research

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09690-0

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