2. Academic Validation
  3. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3

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

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.

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