[HTML][HTML] RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3

CP Dillon, R Weinlich, DA Rodriguez, JG Cripps… - Cell, 2014 - cell.com
CP Dillon, R Weinlich, DA Rodriguez, JG Cripps, G Quarato, P Gurung, KC Verbist…
Cell, 2014cell.com
Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and-
independent signaling pathways leading to cell death and/or inflammation. Genetic ablation
of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8,
or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived
weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-
induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood …
Summary
Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1−/− mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1−/−tnfr1−/− mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.
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