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

Dondelinger Y.; Delanghe T.; Priem D.; Wynosky-Dolfi M.A.; Sorobetea D.; Rojas-Rivera D.; Giansanti P.; Roelandt R.; Gropengiesser J.; Ruckdeschel K.; Savvides S.N.; Heck A.J.R.; Vandenabeele P.; Brodsky I.E.; Bertrand M.J.M.

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.

Más información

Título según WOS: Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
Título según SCOPUS: Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
Título de la Revista: NATURE COMMUNICATIONS
Volumen: 10
Editorial: NATURE PORTFOLIO
Fecha de publicación: 2019
Idioma: English
DOI:

10.1038/s41467-019-09690-0

Notas: ISI, SCOPUS