A JNK-dependent Pathway Is Required for TNFalpha-induced Apoptosis

Cell. 2003 Oct 3;115(1):61-70. doi: 10.1016/s0092-8674(03)00757-8.

Abstract

Tumor necrosis factor (TNFalpha) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-kappaB and the kinase, JNK. While activation of caspase 8 is required for TNFalpha-induced apoptosis, and induction of NF-kappaB inhibits cell death, the precise function of JNK activation in TNFalpha signaling is not clearly understood. Here, we report that TNFalpha-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bid protein, mouse
  • Carrier Proteins
  • DIABLO protein, human
  • Diablo protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 8
  • Caspase 9
  • Caspases