Ubiquitination and TNFR1 signaling.
Death receptors are a subset of the tumor necrosis factor receptor (TNFR) family of proteins and share a characteristic cytoplasmic motif called the "death domain". In addition to mediating cell death, these receptors regulate cell proliferation, inflammatory responses, and tumor progression. Receptor occupancy triggers the assembly of several cytoplasmic molecules into distinct complexes, each initiating separate signaling events leading to different biological responses. Post-translational modifications involving ubiquitin, a peptide of 76 amino acids, regulate events at nearly all stages of signaling. All ubiquitin chains function as docking platforms for molecules with specific recognition motifs that either propagate the signal or target the protein for proteasomal degradation. Moreover, enzymes with ubiquitin thioesterase activity (deubiquitinating enzymes, or DUBs) reverse modifications by removing the ubiquitin chains, allowing ubiquitin editing at the molecular level. Ubiquitin protein ligases (E3s), DUBs, and signaling molecules with ubiquitin recognition motifs control TNFR1 mediated cell death and activation of NF-kappaB and JNK. Here, we discuss the current understanding of how these proteins regulate TNFR1 signaling.
Fujita
Ken-ichi
K
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3016A, 9000 Rockville Pike, Bethesda, MD 20892-4256, USA. fujitak@mail.nih.gov
Srinivasula
Srinivasa M
SM
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D016923:Cell Death / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D025801:Ubiquitin / Q000276:immunology*; D043222:Ubiquitin Thiolesterase / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000276:immunology; D054875:Ubiquitination / Q000276:immunology*
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D048670:MAP Kinase Kinase 4; D043222:Ubiquitin Thiolesterase