Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09690-0
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Funding
- Vlaams Instituut voor Bio-technologie (VIB)(Tech Watch)
- Ghent University
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) [G013715N, G044518N, EOS MODEL-IDI 30826052]
- Belgian science policy office (BELSPO) [IAP 7/32]
- Flemish Government [Methusalem BOF09/01M00709, BOF16/MET_V/007]
- FWO [G013715N]
- Netherlands Organization for Scientific Research (NWO) through the large-scale proteomics facility Proteins@Work [184.032.201]
- Deutsche Forschungsgemeinschaft
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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.
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