Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
2019
RIPK1regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold,
RIPK1inhibits
caspase-8-dependent apoptosis and RIPK3/MLKL-dependent
necroptosis. As a kinase,
RIPK1paradoxically induces these cell death modalities. The
molecular switchbetween
RIPK1pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of
RIPK1on Ser25 by IKKs as a key mechanism directly inhibiting
RIPK1kinase 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
RIPK1is 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
Yersiniainfection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
64
References
61
Citations
NaN
KQI