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PMID:11101870

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Citation

Holler, N, Zaru, R, Micheau, O, Thome, M, Attinger, A, Valitutti, S, Bodmer, JL, Schneider, P, Seed, B and Tschopp, J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1:489-95

Abstract

Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand-induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor kappa B activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.

Links

PubMed Online version:10.1038/82732

Keywords

Adaptor Proteins, Signal Transducing; Animals; Antigens, CD95/metabolism; Apoptosis/physiology; Apoptosis Regulatory Proteins; Carrier Proteins/metabolism; Caspase 8; Caspase 9; Caspases/metabolism; Cell Death/physiology; Fas Ligand Protein; Fas-Associated Death Domain Protein; Humans; Jurkat Cells; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred BALB C; Models, Biological; Necrosis; Proteins/metabolism; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; T-Lymphocytes/cytology; T-Lymphocytes/metabolism; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TNR6

part_of

GO:0031264: death-inducing signaling complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TNFL6

involved_in

GO:0070266: necroptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFL6

involved_in

GO:0097527: necroptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000084)

Seeded From UniProt

complete

HUMAN:TNFL6

involved_in

GO:0097190: apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RIPK1

part_of

GO:0031264: death-inducing signaling complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RIPK1

involved_in

GO:0097527: necroptotic signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CASP8

part_of

GO:0031264: death-inducing signaling complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CASP8

involved_in

GO:0097190: apoptotic signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0097527: necroptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FADD

involved_in

GO:0097527: necroptotic signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FADD

involved_in

GO:0097190: apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FADD

part_of

GO:0031264: death-inducing signaling complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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