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Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation.

Stimulation of cells with tumor necrosis factor (TNFalpha) triggers a recruitment of various signaling molecules, such as RIP, to the TNFalpha receptor 1 complex, leading to activation of NF-kappaB. Previous studies indicate that RIP plays an essential role for TNFalpha-induced NF-kappaB activation, but the molecular mechanism by which RIP mediates TNFalpha signals to activate NF-kappaB is not fully defined. Earlier studies suggest that RIP undergoes a ligand-dependent ubiquitination. However, it remains to be determined whether the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation. In this study, we have identified Lys377 of RIP as the functional ubiquitination site, because mutating this residue to arginine completely abolished RIP-mediated NF-kappaB activation. The K377R mutation of RIP cannot undergo ligand-dependent ubiquitination and fails to recruit its downstream signaling components into the TNFalpha receptor 1 complex. Together, our studies provide the first genetic evidence that the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation.

Pubmed ID: 16543241


  • Li H
  • Kobayashi M
  • Blonska M
  • You Y
  • Lin X


The Journal of biological chemistry

Publication Data

May 12, 2006

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI058048
  • Agency: NIGMS NIH HHS, Id: GM065899

Mesh Terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Gene Expression Regulation
  • Humans
  • Jurkat Cells
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha
  • Ubiquitin