Activation of a pro-apoptotic amplification loop through inhibition of NF-kappaB-dependent survival signals by caspase-mediated inactivation of RIP.
Death domain containing members of the tumor necrosis factor receptor (TNFR) superfamily can induce apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. Frequently, NF-kappaB activation conveys protection against cell death. We show that the serine/threonine kinase RIP that is required for TNF-induced NF-kappaB activation is processed by caspase-8 into a dominant-negative (DN) fragment during death receptor-induced apoptosis, thereby leading to a blockade of NF-kappaB-mediated anti-apoptotic signals. Our results suggest that cleavage of RIP is part of an amplification loop which is triggered by Fas and most likely by other death receptors.
Martinon
F
F
Institute of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066, Epalinges, Switzerland.
Holler
N
N
Richard
C
C
Tschopp
J
J
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D016328:NF-kappa B; D011506:Proteins; D011994:Recombinant Proteins; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases