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

  • Cell. 2014 May 22;157(5):1189-202. doi: 10.1016/j.cell.2014.04.018.
Christopher P Dillon  1 ,  Ricardo Weinlich  1 ,  Diego A Rodriguez  1 ,  James G Cripps  1 ,  Giovanni Quarato  1 ,  Prajwal Gurung  1 ,  Katherine C Verbist  1 ,  Taylor L Brewer  1 ,  Fabien Llambi  1 ,  Yi-Nan Gong  1 ,  Laura J Janke  2 ,  Michelle A Kelliher  3 ,  Thirumala-Devi Kanneganti  1 ,  Douglas R Green  4
Affiliations
  • 1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2. Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 4. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: [email protected].
PMID: 24813850 DOI: 10.1016/j.cell.2014.04.018
Abstract

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.