title: Cell fate decisions regulated by K63 ubiquitination of tumor necrosis factor receptor 1.
abstract: Signaling by tumor necrosis factor (TNF) receptor 1 (TNF-R1), a prototypic member of the death receptor family, mediates pleiotropic biological outcomes ranging from inflammation and cell proliferation to cell death. Although many elements of specific signaling pathways have been identified, the main question of how these selective cell fate decisions are regulated is still unresolved. Here we identified TNF-induced K63 ubiquitination of TNF-R1 mediated by the ubiquitin ligase RNF8 as an early molecular checkpoint in the regulation of the decision between cell death and survival. Downmodulation of RNF8 prevented the ubiquitination of TNF-R1, blocked the internalization of the receptor, prevented the recruitment of the death-inducing signaling complex and the activation of caspase-8 and caspase-3/7, and reduced apoptotic cell death. Conversely, recruitment of the adaptor proteins TRADD, TRAF2, and RIP1 to TNF-R1, as well as activation of NF-κB, was unimpeded and cell growth and proliferation were significantly enhanced in RNF8-deficient cells. Thus, K63 ubiquitination of TNF-R1 can be sensed as a new level of regulation of TNF-R1 signaling at the earliest stage after ligand binding.
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Jürgen
authors: J
authors: Fritsch
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Mario
authors: M
authors: Stephan
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Vladimir
authors: V
authors: Tchikov
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Supandi
authors: S
authors: Winoto-Morbach
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Svetlana
authors: S
authors: Gubkina
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.
authors: Dieter
authors: D
authors: Kabelitz
authors: Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany schuetze@immunologie.uni-kiel.de.
authors: Stefan
authors: S
authors: Schütze
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C119724:AGFG1 protein, human; D004268:DNA-Binding Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C486521:RNF8 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases; C505530:CASP8 protein, human; D053181:Caspase 8