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

• Published in: Nature communications 2019-04, Vol.10 (1), p.1729-1729, Article 1729
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 38; 38/1; 631/250/1933; 631/337/458/1733; 631/80/82/23; 631/80/82/2344; 82/51; 82/58; 82/80; 82/83; 96/109; 96/2; 96/21; 96/95; Animal models; Animals; Apoptosis; Caspase; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase 8 - physiology; Caspase-8; Cell culture; Cell death; Cell Line; Cytotoxicity; Humanities and Social Sciences; I-kappa B Kinase - metabolism; I-kappa B Kinase - physiology; Immunity - physiology; Infections; Inflammation; Inhibition; Kinases; Mice; Mimicry; Models, Immunological; Molecular machines; Mortality; multidisciplinary; Mutation; Necroptosis; Phenotypes; Phosphorylation; Receptor-Interacting Protein Serine-Threonine Kinases - chemistry; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - physiology; Science; Science (multidisciplinary); Serine; Serine - chemistry; Serine - metabolism; TAK1 protein; Tumor necrosis factor; Yersinia; Yersinia Infections - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09690-0

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.