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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 RIS Download

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

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Associated grants

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

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